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Home , Adverse drug reaction, Adverse effect, Allergy, Aminophenazone, Argatroban, Baboon syndrome

Drug : An Updated Practice Parameter These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, and , the American College of Allergy, Asthma and Immunology, and the Joint Council of Allergy, Asthma and Immunology.

Chief Editors Roland Solensky, MD, and David A. Khan, MD

Workgroup Contributors I. Leonard Bernstein, MD; Gordon R. Bloomberg, MD; Mariana C. Castells, MD, PhD; Louis M. Mendelson, MD; and Michael E. Weiss, MD

Task Force Reviewers David I. Bernstein, MD; Joann Blessing-Moore, MD; Linda Cox, MD; David M. Lang, MD; Richard A. Nicklas, MD; John Oppenheimer, MD; Jay M. Portnoy, MD; Christopher Randolph, MD; Diane E. Schuller, MD; Sheldon L. Spector, MD; Stephen Tilles, MD; and Dana Wallace, MD

Reviewers Paul J. Dowling, MD – Kansas City, MO Mark Dykewicz, MD – -, NC Paul A. Greenberger, MD – Chicago, IL Eric M. Macy, MD – San Diego, CA Kathleen R. May MD – Cumberland, MD Myngoc T. Nguyen, MD – Piedmont, CA Lawrence B. Schwartz, MD, PhD – , VA

TABLE OF CONTENTS Summary Statements of the Evidence-Based Commentary Preface Evidence-Based Commentary Glossary I. Introduction Executive Summary II. Definitions Algorithm for Management of Hyper- III. Classification of Immunologically Mediated Drug sensitivity Reactions Annotations for Disease Management of Drug Hyper- A. IgE-mediated reactions (Gell-Coombs type I) sensitivity B. Cytotoxic reactions (Gell-Coombs type II) C. reactions (Gell-Coombs type III) D. -mediated reactions (Gell-Coombs type IV) These parameters were developed by the Joint Task Force on Practice E. Miscellaneous syndromes Parameters, representing the American Academy of Allergy, Asthma and 1. Immunology; the American College of Allergy, Asthma and Immunology; and the Joint Council of Allergy, Asthma and Immunology. 2. Drug with and systemic symptoms The American Academy of Allergy, Asthma and Immunology (AAAAI) 3. Pulmonary drug hypersensitivity and the American College of Allergy, Asthma and Immunology (ACAAI) 4. Drug-induced erythematosus have jointly accepted responsibility for establishing “: An 5. Drug-induced granulomatous disease with or Updated Practice Parameter.” This is a complete and comprehensive docu- ment at the current time. The medical environment is a changing environ- without vasculitis ment, and not all recommendations will be appropriate for all . 6. Immunologic Because this document incorporated the efforts of many participants, no 7. Blistering disorders single individual, including those who served on the Joint Task Force, is a. multiforme minor authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of b. major/Stevens-Johnson these practice parameters by the AAAAI or ACAAI should be directed to the syndrome Executive Offices of the AAAAI, the ACAAI, and the Joint Council of c. Toxic epidermal necrolysis Allergy, Asthma and Immunology. These parameters are not designed for 8. sickness–like reactions associated with use by pharmaceutical companies in drug promotion. Reprint requests: Joint Council of Allergy, Asthma & Immunology, 50 specific N. Brockway St, #3-3, Palatine, IL 60067. 9. Immunologic nephropathy

273.e1 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY F. Other classification systems for drug allergy U. Complementary IV. Factors V. Other agents V. Clinical Evaluation and Diagnosis of Drug Allergy A. History CONTRIBUTORS B. The Joint Task Force has made a concerted effort to acknowl- C. General clinical tests edge all contributors to this parameter. If any contributors D. Specific tests have been excluded inadvertently, the Task Force will ensure E. diagnosis that appropriate recognition of such contributions is made VI. Management and Prevention of Drug Allergic subsequently. Reactions A. General CHIEF EDITORS B. Induction of Roland Solensky, MD C. Immunologic IgE induction of drug tolerance Division of Allergy and Immunology (drug desensitization) The Corvallis D. Immunologic non-IgE induction of drug tolerance Corvallis, Oregon for nonanaphylactic reactions David A. Khan, MD E. Pharmacologic induction of drug tolerance (eg, Professor of desensitization) Division of Allergy & Immunology F. Undefined induction of drug tolerance University of Texas Southwestern Medical Center G. Graded challenge Dallas, Texas VII. Specific A. ␤-Lactam WORKGROUP CONTRIBUTORS 1. I. Leonard Bernstein, MD 2. and Professor of Clinical Medicine 3. Cephalosporins University of Cincinnati College of Medicine 4. administration to patients with a Cincinnati, Ohio allergy Gordon R. Bloomberg, MD 5. Penicillin administration to patients with a Associate Professor, Department of history of cephalosporin allergy Division of Allergy & Pulmonary Medicine 6. () Washington University School of Medicine 7. Saint Louis, Missouri B. Non–␤-lactam antibiotics Mariana C. Castells, MD, PhD C. drugs Director, Desensitization Program D. Associate Director, Allergy Immunology Training Program E. chemotherapeutic agents Brigham & Women’s F. (HIV) medications Harvard G. Disease-modifying antirheumatic drugs (DMARDs) Boston, Massachusetts H. Immunomodulatory agents for autoimmune Louis M. Mendelson, MD I. Modifying drugs for dermatologic diseases Clinical Professor J. Perioperative agents University of Connecticut K. and blood products Partner, Connecticut Asthma & Allergy Center, LLC L. Hartford, Connecticut M. Michael E. Weiss, MD N. Protamine Clinical Professor of Medicine, O. University of Washington, School of Medicine P. Local Seattle, Washington Q. Radiocontrast media (RCM) R. Aspirin and nonsteroidal anti-inflammatory drugs TASK FORCE REVIEWERS (NSAIDs) David I. Bernstein, MD S. Angiotensin-converting (ACE) inhibitors Department of Clinical Medicine, Division of Immunology T. Biologic modifiers University of Cincinnati College of Medicine 1. Cincinnati, Ohio 2. Anti–TNF-␣ drugs Joann Blessing-Moore, MD 3. Monoclonal Department of Immunology 4. Stanford University Medical Center 5. Anticancer monoclonal antibodies Palo Alto, California

VOLUME 105, OCTOBER, 2010 273.e2 Linda Cox, MD Acknowledgments Department of Medicine The Joint Task Force wishes to acknowledge the following Nova Southeastern University individuals who also contributed substantially to the creation Davie, Florida of this parameter: Erin Shae Johns, PhD, and Jessica Karle, David M. Lang, MD MS, for their immense help with formatting and restructuring Allergy/Immunology Section, Division of Medicine this document; Susan Grupe for providing key administrative Cleveland Clinic Foundation help to the contributors and reviewers of this parameter; and Cleveland, Ohio Brett Buchmiller, MD, for his assistance in creating the Richard A. Nicklas, MD algorithms in this parameter. Department of Medicine PREFACE George Washington Medical Center Washington, DC The objective of “Drug Allergy: An Updated Practice Param- John Oppenheimer, MD eter” is to improve the care of patients by providing the practicing with an evidence-based approach to the Department of diagnosis and management of adverse drug reactions. This New Jersey Medical School document was developed by a Working Group under the Morristown, New Jersey aegis of the Joint Task Force on Practice Parameters, which Jay M. Portnoy, MD has published 26 practice parameters and updated parameters Section of Allergy, Asthma & Immunology for the field of allergy/immunology (these can be found The Children’s Mercy Hospital online at www.jcaai.org). The 3 national allergy and immu- University of Missouri-Kansas City School of Medicine nology societies—the American Academy of Allergy, Kansas City, Missouri Asthma and Immunology (AAAAI), the American College of Christopher Randolph, MD Allergy, Asthma and Immunology (ACAAI), and the Joint Center for Allergy, Asthma and Immunology Council of Allergy, Asthma and Immunology (JCAAI)— Yale Hospital have given the Joint Task Force the responsibility for both Waterbury, Connecticut creating new parameters and updating existing parameters. Diane E. Schuller, MD This parameter builds on “Disease Management of Drug Department of Pediatrics Hypersensitivity: A Practice Parameter,” which was pub- Pennsylvania State University lished in 1999 by the Joint Task Force on Practice Parame- Milton S. Hershey Medical College ters. It follows the same general format as that document, Hershey, Pennsylvania with some substantive changes reflecting advancements in Sheldon L. Spector, MD scientific knowledge and their effect on management of drug Department of Medicine allergy. This document was written and reviewed by special- UCLA School of Medicine ists in the field of allergy and immunology and was exclu- Los Angeles, California sively funded by the 3 allergy and immunology organizations Stephen A. Tilles, MD noted above. Department of Medicine A Working Group chaired by Roland Solensky, MD, pre- University of Washington School of Medicine pared the initial draft, which was then reviewed by the Joint Redmond, Washington Task Force. A comprehensive search of the medical literature Dana Wallace, MD was conducted using Ovid MEDLINE and the Cochrane Database and Keywords relating to drug allergy. Published Department of Medicine clinical studies were rated by category of evidence and used Nova Southeastern University to establish the strength of clinical recommendations. The Davie, Florida working draft of “Drug Allergy: An Updated Practice Param- eter” was reviewed by a large number of experts in allergy Invited Reviewers and immunology. These experts included reviewers ap- Paul J. Dowling, MD – Kansas City, MO pointed by the AAAAI and ACAAI. The authors carefully Mark S. Dykewicz, MD – Winston Salem, NC reviewed and considered additional comments from these Paul A. Greenberger, MD – Chicago, IL reviewers. The revised final document presented here was Eric M. Macy, MD – San Diego, CA approved by the sponsoring organizations and represents an Kathleen R. May, MD – Cumberland, MD evidence-based; broadly accepted consensus parameter. Myngoc T. Nguyen, MD – Piedmont, CA This updated parameter contains several significant changes from the original parameter on “Disease Manage- ment of Drug Hypersensitivity: A Practice Parameter.” The Ad Hoc Reviewers title of the parameter was changed from drug hypersensitivity Lawrence B. Schwartz, MD to drug allergy. In this updated parameter the term drug

273.e3 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY allergy is defined as an immunologically mediated response • Drug allergy is an immunologically mediated response to to a pharmaceutical and/or formulation (excipient) agent in a a pharmaceutical and/or formulation (excipient) agent in a sensitized person. The implication is that drug allergy does sensitized person. not simply include only IgE-mediated reactions. Another • is an immediate systemic reaction that occurs significant change is the introduction of the new term induc- when a previously sensitized individual is reexposed to an tion of drug tolerance to encompass classic IgE-mediated . It is caused by rapid IgE-mediated immune re- drug desensitizations and other non–IgE-mediated “desensi- lease of vasoactive mediators from tissue mast cells and tization” procedures for various medications. In addition, peripheral with a potential late component. several new sections have been added, including a new glos- • Pseudoallergic (anaphylactoid) reactions are immediate sary with new terms, new classifications and subclassifica- systemic reactions that mimic anaphylaxis but are caused tions for drug reactions, and new sections on drug aller- by non–IgE-mediated release of mediators from mast cells gic reactions to chemotherapeutic agents, corticosteroids, and basophils. disease-modifying antirheumatic drugs, antimycobacterial • is an undesirable pharmacologic effect drugs, biologic modifiers, immunosuppressive agents, immu- that may occur at low or usual doses of the drug without nomodulatory agents, complementary medications, and drug- underlying abnormalities of , , or bio- induced with or without vasculitis. Significant availability of the drug. Humoral or cellular immune updates to sections on cutaneous manifestations of drug re- mechanisms are not thought to be involved, and a scien- actions, laboratory testing, ␤-lactam allergy, cross-reactivity tific explanation for such exaggerated responses has not between carbapenems and penicillin, and human immunode- been established (eg, aspirin-induced tinnitus at low ficiency virus medications have been added. Finally, a num- doses). ber of protocols for induction of drug tolerance procedures • Drug idiosyncrasy is an abnormal and unexpected effect have been added. that is unrelated to the intended pharmacologic action of a The Executive Summary emphasizes the key updates since drug and has an unknown mechanism. It is not mediated the 1999 drug hypersensitivity parameter. This Executive by a humoral or cellular but is repro- Summary has been significantly expanded to include the new ducible on readministration. It may be due to underlying sections and highlight the major updates to this parameter. It abnormalities of metabolism, excretion, or should be noted that the Executive Summary does not discuss (eg,: -induced drug ). all of this parameter’s topics in depth. An annotated algo- • Aspirin-exacerbated respiratory disease (AERD) is a clin- rithm in this document summarizes the major decision points ical entity characterized by aspirin- or nonsteroidal anti- for the evaluation and treatment of patients who have expe- inflammatory–induced respiratory reactions in patients rienced possible adverse drug reactions (Fig 1). This is fol- with underlying asthma and/or or . AERD lowed by a list of summary statements that represent the key does not fit precisely into a specific category of adverse points to consider in the evaluation and management of drug drug reactions. hypersensitivity reactions. Within the evidence-based com- • Drug tolerance is defined as a state in which a with mentary, the summary statements are repeated and are fol- a drug allergy will tolerate a drug without an adverse lowed by the text that supports that summary statement. The reaction. Drug tolerance does not indicate either a perma- evidence-based commentary first discusses general issues nent state of tolerance or that the mechanism involved was relating to drug allergy, including definitions, classifications, immunologic tolerance. risk factors, and the general approach to evaluation, diagno- • Induction of drug tolerance, which has often been referred sis, management, and prevention (sections I through VI). to as drug desensitization, is appropriately described Subsequently, specific types of drugs are discussed (section as a temporary induction of drug tolerance. Induction of VII). drug tolerance can involve IgE immune mechanisms, non- The Joint Task Force on Practice Parameters would like to IgE immune mechanisms, pharmacologic mechanisms, thank the AAAAI, ACAAI, and JCAAI, who supported the and undefined mechanisms. All procedures to induce drug preparation of the updated parameter, and the large number of tolerance involve administration of incremental doses of individuals who have so kindly dedicated their time and effort the drug. See Table 1 for characteristics of these 4 types of to the preparation and review of this document. drug tolerance. • Drug desensitization is one form of induction of immune GLOSSARY drug tolerance (see above) by which effector cells are • Adverse drug reactions include all unintended pharmaco- rendered less reactive or nonreactive to IgE-mediated im- logic effects of a drug except therapeutic failures, inten- mune responses by rapid administration of incremental tional overdosage, abuse of the drug, or errors in admin- doses of an allergenic substance. istration. They can be classified as predictable or • Graded challenge or test dosing describes administration unpredictable. Unpredictable reactions are further subdi- of progressively increasing doses of a until a vided into drug intolerance, drug idiosyncrasy, drug al- full is reached. The intention of a graded challenge is lergy, and pseudoallergic reactions. to verify that a patient will not experience an immediate

VOLUME 105, OCTOBER, 2010 273.e4 Figure 1. Algorithm for disease management of drug allergy.

273.e5 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Table 1. Classification of Induction of Drug Tolerance (Formerly Referred to as Desensitization)a Type of drug Time/duration Initial dose Possible outcomes Example tolerance

Immunologic IgE (drug Hours Micrograms -specific mediator depletion, Penicillin desensitization) downregulation of receptors Immunologic non-IgE Hours to days Milligrams Unknown - Pharmacologic Hours to days Milligrams Metabolic shift, internalization of Aspirin receptors Undefined Days to Weeks Micrograms to milligrams Unknown Allopurinol a What has often been referred to as drug desensitization is more appropriately described as induction of drug tolerance. Induction of drug tolerance can involve IgE immune mechanisms, non-IgE immune mechanisms, pharmacologic mechanisms, and mixed or unknown mechanisms. All involved administration of incremental doses of the drug. This table indicates the characteristics of these 4 types of drug tolerance.

adverse reaction to a given drug. The medication is intro- There have, however, been great strides made in our under- duced in a controlled manner to a patient who has a low standing of other drug and adverse drug reactions likelihood of reacting to it. Unlike procedures that induce such as aspirin-exacerbated respiratory disease (AERD). drug tolerance, graded challenges usually involve fewer Drug allergy may be classified by the Gell-Coombs clas- doses, are of shorter duration, and are not intended to sification of human hypersensitivity: IgE-mediated (type I), induce drug tolerance. cytotoxic (type II), immune complex (type III), and cellular • The drug rash with eosinophilia and systemic symptoms mediated (type IV). Delayed hypersensitivity type IV reac- (DRESS) syndrome is a drug-induced, multiorgan inflam- tions are mediated by cellular immune mechanisms. A re- matory response that may be life threatening. First de- cently proposed modification subdivides type IV reactions scribed in conjunction with drug use, it has into 4 categories involving activation and recruitment of since been ascribed to a variety of drugs. (IVa), (IVb), CD4ϩ or CD8ϩ T cells (IVc), and (IVd).1 The classic reaction in this EXECUTIVE SUMMARY category is contact , a condition in which the top- ical induction and elicitation of sensitization by a drug is Classification of Adverse Reactions to Drugs entirely limited to the . It appears that Gell-Coombs type Adverse drug reactions (ADRs) result in major health prob- IV reactions are also responsible for delayed cutaneous erup- lems in the in both the inpatient and outpatient tions, such as maculopapular due to antibiotics settings. ADRs are broadly categorized into predictable (type (eg, amoxicillin and sulfonamides) and acute generalized A) and unpredictable (type B) reactions. Predictable reactions exanthematous pustulosis. Drug allergy may also be classi- are usually dose dependent, are related to the known phar- fied by the predominant tissue or involved (eg, sys- macologic actions of the drug, and occur in otherwise healthy individuals. They are estimated to comprise approximately temic, cutaneous, hepatic), which is useful in light of the 80% of all ADRs. Unpredictable reactions are generally dose difficulty that sometimes occurs in determining the immuno- independent, are unrelated to the pharmacologic actions of logic mechanism involved. Table 2 highlights the spectrum of the drug, and occur only in susceptible individuals. Unpre- drug allergic reactions and syndromes that will be discussed dictable reactions are subdivided into drug intolerance, drug in greater detail in this parameter. idiosyncrasy, drug allergy, and pseudoallergic reactions. Both The p-i concept (pharmacologic interaction with immune type A and type B reactions may be influenced by genetic receptors) is a recently proposed addition to drug hypersen- predisposition of the patient. sitivity classification. In this scheme, a drug binds nonco- In this parameter, drug allergy is defined as an immuno- valently to a T-cell , which may lead to an immune logically mediated response to a pharmaceutical and/or for- response via interaction with an major histocompatibility mulation (excipient) agent in a sensitized person. The classi- receptor. In this scenario, no sensitization is required because fication of drug allergies is impeded by our limited there is direct stimulation of memory and effector T cells, understanding of the underlying mechanisms. Although the analogous to the concept of .2,3 Gell-Coombs classification served a useful purpose in its The structural characteristics of certain drugs, such as time, it does not account for many common clinical problems. penicillin and , may help predict the type of hyper- Nevertheless, when applicable we will still refer to recent sensitivity reaction; however, this is not always the case. modifications of that system. Our knowledge of IgE-medi- Other drug-specific risk factors include the dose, route of ated drug allergy is derived chiefly from the vast amount of administration, duration of treatment, repetitive exposure to research involving penicillin allergy. Beyond this, our knowl- the drug, and concurrent illnesses. risk factors include edge of drug allergy mechanisms is limited but emerging. age, , , specific genetic polymorphisms, and inherent

VOLUME 105, OCTOBER, 2010 273.e6 Table 2. Drug Allergic Reactions and Syndromes Clinical manifestations Examples of causative agents

IgE mediated Urticaria, , bronchospasm, anaphylaxis ␤-Lactam antibiotics, platinum-based chemotherapeutics, perioperative agents Cytotoxic Hemolytic , , Penicillin, , sulfonamides granulocytopenia Immune complex Penicillin, , thymoglobulin Delayed type hypersensitivity , exanthems , , penicillin, antibiotics Hypersensitivity vasculitis Cutaneous or visceral vasculitis , , propylthiouracil DRESS Cutaneous, fever, eosinophilia, hepatic dysfunction, , sulfonamides, , allopurinol Pulmonary drug Pneumonitis, fibrosis , , hypersensitivity Systemic drug-induced lupus , myalgias, fever, Hydralazine, , erythematosus Cutaneous drug-induced lupus Erythematous/scaly plaques in photodistribution , calcium channel blockers, erythematosus ACE inhibitors Drug-induced granulomatous Churg-Strauss syndrome, Wegener’s Propylthiouracil, modifiers disease granulomatosis Immunologic hepatitis Hepatitis, cholestatic Para-aminosalicylic , sulfonamides, Blistering disorders Erythema multiforme, SJS, TEN Sulfonamides, cephalosporins, anticonvulsants, NSAIDs Serum sickness–like reactions Erythema multiforme, arthralgias , Immunologic nephropathy Interstitial nephritis, membranous Penicillin, sulfonamides, gold, penicillamine, allopurinol Abbreviations: ACE, angiotensin-converting enzyme; DRESS, drug rash with eosinophilia and systemic symptoms; NSAIDs, nonsteroidal anti-inflammatory drugs; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. predisposition to react to multiple unrelated drugs (multiple life-threatening cutaneous reactions such as Stevens-Johnson drug allergy syndrome). syndrome (SJS), toxic epidermal necrolysis (TEN), exfolia- tive dermatitis, and drug rash with eosinophilia and systemic History and Physical Examination symptoms (DRESS).4 The history, physical examination, and objective clinical and laboratory tests are important components in the clinical Diagnostic Tests evaluation and diagnosis of drug hypersensitivity. The history Possible clinical tests might include but are not limited to a should focus on such items as previous and current drug use, chest x-ray examination, a complete blood cell count with the and allergenicity of previously and currently used differential, sedimentation rate, nuclear and cytoplasmic au- drugs, and the temporal sequence of events between initiation toantibody tests, and other specific immunologic tests. A of and onset of symptoms. Physical examination retrospective diagnosis of anaphylaxis may be determined by should include all systems that could possibly account for the detecting an increase in serum total tryptase levels above clinical presentation. Cutaneous manifestations are the most baseline or in serum mature tryptase (also known as common presentation for drug allergic reactions. Although ␤-tryptase). The most useful test for detecting IgE-mediated drug allergic reactions may present with noncutaneous phys- drug reactions caused by many large-molecular-weight bio- ical findings, these findings are generally nonspecific and are logicals and penicillin is the immediate hypersensitivity skin not nearly as helpful in diagnosis and management decisions. test. Relatively few studies with small numbers of patients Therefore, the emphasis in this parameter on the physical have evaluated the specificity and sensitivity of third-gener- examination focuses on cutaneous findings. ation assays for detection of penicillin specific IgE .5,6 Characterization of cutaneous lesions is important in re- These studies demonstrate relatively high specificity (97%- gard to determining the cause, further diagnostic tests, and 100%) but lower sensitivity (29%-68%) for penicillin specific management decisions. Numerous cutaneous reaction pat- IgE. Therefore, although a positive in vitro test result for terns have been reported in drug allergy, including exan- penicillin specific IgE is highly predictive of penicillin al- thems, urticaria, angioedema, , bullous eruptions, fixed lergy, a negative in vitro test result does not adequately drug eruptions, erythema multiforme, , exclude penicillin allergy. The activation test is a photosensitivity, , , vasculitis, pruritus, and recently described method of evaluating expression of CD63

273.e7 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY on basophils after stimulation with an allergen.7 There are creased risk for future reactions compared with the general limited data using this method to evaluate patients with population. possible allergies to ␤-lactam antibiotics and nonsteroidal The choice of whether to introduce a clinically indicated anti-inflammatory drugs (NSAIDs).8-10 Further confirmatory drug via graded challenge or via induction of drug tolerance studies, especially with commercially available tests, are mainly depends on the likelihood that the patient is allergic at needed before its general acceptance as a diagnostic tool. the time of the procedure. Patients who, based on their history Patch testing is the most reliable technique for diagnosis of and/or diagnostic test results, are unlikely to be allergic to a contact dermatitis caused by topically applied drugs. The drug may undergo graded challenge. Patients who have a diagnosis of contact dermatitis usually can be verified by relatively higher likelihood of being allergic to a drug should patch testing. In recent years there have been reports con- undergo an induction of drug tolerance procedure. Graded cerning the diagnostic utility of patch tests with systemically challenge (or induction of drug tolerance) should almost administered drugs in non–IgE-mediated cutaneous drug re- never be performed if the reaction history is consistent with actions.11 Drug patch testing may be useful for certain types a severe non–IgE-mediated reaction, such as SJS, TEN, in- of cutaneous drug reactions, including maculopapular exan- terstitial nephritis, hepatitis, or . thems, acute generalized exanthematous pustulosis, and fixed drug eruptions,12-14 but generally is not helpful for SJS or Other Immunologic Drug Allergy Syndromes urticarial eruptions.12-15 Specific drugs or classes of drugs may be associated with In complex cases where multiple drugs are involved with- characteristic syndromes, which may not conform to typical out a clear-cut temporal relationship, a may be presentations defined by the Gell-Coombs classification sys- useful in suggesting a drug-induced eruption. However, there tem. Table 2 lists the various other immunologic drug allergic are no absolute histologic criteria for the diagnosis of drug- syndromes discussed in the parameter. induced eruptions, and a skin biopsy may not definitively exclude alternative causes.16 Specific Drugs and Biologic Agents Drug allergic reactions have been reported to most all med- Induction of Drug Tolerance and Graded Challenges ications. However, certain drugs are more frequently associ- What has often been referred to as drug desensitization is ated with specific types of reactions. Significant updates on more appropriately described in this parameter as a temporary the following drugs and biologic agents have been made in induction of drug tolerance. Drug tolerance is defined as a this updated parameter and are discussed elsewhere in more state in which a patient with a drug allergy will tolerate a drug detail. without an adverse reaction. Drug tolerance does not indicate either a permanent state of tolerance or that the mechanism involved was immunologic tolerance. Induction of drug tol- The most important causes of immediate hypersensitivity erance procedures modify a patient’s response to a drug to reactions are antibiotics, particularly ␤-lactam antibiotics. temporarily allow treatment with it safely. They are indicated Approximately 10% of patients report a history of penicillin only in situations where an alternate non–cross-reacting allergy. However, up to 90% of these individuals are able to medication cannot be used. Induction of drug tolerance can tolerate penicillin and are designated as having “penicillin involve IgE immune mechanisms, non-IgE immune mecha- allergy” unnecessarily.17,18 Use of broad-spectrum antibiotics nisms, pharmacologic mechanisms, and undefined mecha- in patients designated as being “penicillin allergic” is asso- nisms (Table 1). All procedures to induce drug tolerance ciated with higher costs, increased resistance, and involve administration of incremental doses of the drug. may compromise optimal medical care.19 Penicillin skin test- Through various mechanisms, these procedures induce a tem- ing is the most reliable method for evaluating IgE-mediated porary state of tolerance to the drug, which is maintained only penicillin allergy. Ideally, both major and minor determinant as long as the patient continues to take the specific drug. reagents are used for skin testing. Penicillin challenges of Where there is a definite medical indication for the agent in individuals skin test negative to penicilloylpolylysine and question, either induction of drug tolerance or graded chal- penicillin G20,21 have similar reaction rates compared with lenge procedures may be considered, depending on the his- individuals skin test negative to the full set of major and tory of the previous reaction and the likelihood that the minor penicillin determinants.17,18 patient is currently allergic to that agent. If there is a low Varying degrees of allergic cross-reactivity between peni- likelihood of drug allergy, a graded challenge or test dose to cillin and cephalosporins have been documented. Overall, the specific drug in question may provide a useful confirma- most patients with a history of penicillin allergy tolerate tion that administration of the drug will not result in an cephalosporins,22 but there are rare reports of anaphylactic immediate reaction. The purpose of graded challenge is to reactions, including fatal reactions.23 Patients with a history cautiously administer a drug to a patient who is unlikely to be of penicillin allergy who have negative skin test results to allergic to it and there is no intention to induce tolerance to penicillin using major and minor determinants may receive the drug. Patients who tolerate a graded challenge are con- cephalosporins safely.24 Skin testing for cephalosporins and sidered to not be allergic to the drug and are not at in- other ␤-lactam antibiotics is not standardized, as it is for

VOLUME 105, OCTOBER, 2010 273.e8 penicillin. There is no allergic cross-reactivity between pen- reactions may be the result of excipients rather than the active icillin and monobactams. The degree of cross-reactivity be- drug, such as Cremophor-EL, a lipid solvent vehicle used in tween penicillin and carbapenems appears to be low.25,26 and other intravenous chemotherapeutics. In the IgE-mediated reactions to non–␤-lactam antibiotics may oc- , paclitaxel and produce anaphylactic cur but are less common. There is no standardized skin reactions in as many as 42% of patients on first administra- testing for evaluation of immediate-type allergy to non–␤- tion,54 suggesting an anaphylactoid mechanism. Pretreatment lactam antibiotics. with systemic corticosteroids and prevents the Sulfonamide antibiotics rarely cause IgE-mediated reac- reaction in more than 90% of patients.55 Patients who react tions and more commonly result in delayed maculopapular despite pretreatment can usually be successfully desensi- exanthems, particularly in human immunodeficiency virus tized.56-58 Another option for patients who react to paclitaxel (HIV)–positive patients. There is no evidence to suggest is to switch to docetaxel because most are able to tolerate it.59 allergic cross-reactivity between sulfonamide antibiotics and Platinum compounds (, , and ) nonantibiotic sulfonamides.27 rarely causes IgE- typically cause hypersensitivity reactions after completion of mediated reactions, but more than 50% of patients experience several treatment courses,60,61 suggesting an immunologic immediate cutaneous erythema, , and pruritus (red mechanism. Pretreatment with corticosteroids and antihista- man syndrome), which is the result of non–IgE-mediated mines does not prevent these reactions.62 Skin testing with the release. Red man syndrome reactions can be pre- undiluted drug has been found to identify patients at risk of vented by slowing the and premedicating with reactions, and skin testing should be repeated before each 61,63,64 histamine1 receptor antihistamines. Although aminoglyco- subsequent course with the drug. For patients with pos- sides rarely cause hypersensitivity reactions, there are indi- itive skin test results, various rapid induction of drug toler- vidual case reports of IgE-mediated systemic reactions. Re- ance protocols have been reported, but they are not uniformly ports of IgE-mediated anaphylactic reactions to quinolones successful.61,63,64 Recently, a 12-step desensitization protocol appear to be increasing, possibly due to increased use of these for a variety of chemotherapeutic agents, including platinum agents.28-31 In vitro studies suggest a large extent of allergic compounds, has been reported to be completely successful in cross-reactivity among quinolones,2,28 but there are no clinical 413 procedures, with 94% of procedures having only a mild studies to confirm this. Delayed cutaneous eruptions appear or no reaction.58 in approximately 2% of quinolone-treated patients.32,33 There Methotrexate is a cause of noncytotoxic pulmonary reac- is evidence to show that drug-specific T cells are responsible tions.65,66 Methotrexate pneumonitis occurs most frequently for delayed maculopapular exanthems from quinolones.2 within the first year of treatment, and the reported incidence Allergic drug reactions to antimycobacterial drugs can induce of this reaction varies from 0.86% to 6.9%.67,68 If use of the both minor and life-threatening reactions. Many allergic reac- drug is inadvertently continued, interstitial fibrosis may ensue. tions were also encountered after use of second-generation drugs, including isoniazid, , , and ri- Medications for Patients With HIV and AIDS fampicin.34 These include anaphylaxis, angioedema, pulmonary Drug reactions are common in patients infected with the HIV infiltrates, and cutaneous reactions.35-39 virus, and in some cases, the incidence of reactions may be related to the degree of immunodeficiency.69-73 Adverse re- and Oral Antidiabetic Drugs actions to sulfonamides may complicate both treatment and Since the introduction of purified human recombinant insulin, prophylaxis of Pneumocystis jiroveci in many allergy to insulin is rare and is now encountered in less than patients with AIDS. The most common reaction to sulfon- 1% of patients.40-43 However, life-threatening allergic reac- is a , maculopapular eruption often as- tions to human insulin and insulin analogs (Aspart, Lispro, sociated with fever that occurs after 7 to 12 days of therapy. and Glargine) have been documented and can be confirmed For HIV-positive individuals who develop typical delayed by appropriate intracutaneous and/or in vitro testing.44,45 The maculopapular after trimethoprim and sulfamethox- mechanisms of immunogenic reactions to recombinant hu- administration, many different induction of drug toler- man insulin are not entirely clear but may relate to structural ance protocols have been developed and used successfully.74-85 It changes of insulin, including insulin aggregation (fibrilla- is not clear how or to what extent the immune response to tion).46 Leukocytoclastic vasculitis, generalized arteritis, trimethoprim-sulfamethoxazole is modified during these granulomatous hepatitis, and autoimmune vul- types of induction of drug tolerance procedures. In a random- garis are rare immune-mediated reactions that have been ized trial of trimethoprim-sulfamethoxazole induction of drug described to occur during treatment with and/or tolerance vs rechallenge (single dose), the success rates were sulfonylurea antidiabetic agents.47-53 79% and 72%, respectively, and the difference was not sta- tistically significant.83 , acyclovir, , Cancer Chemotherapeutic Agents , and induction of drug tolerance proto- Hypersensitivity reactions have been reported for virtually all cols have also been developed for patients with AIDS.86-91 commonly used chemotherapeutic agents. Reactions range At least 20 antiretroviral drugs are approved by the US from mild cutaneous eruptions to fatal anaphylaxis. Some and Drug Administration for highly active antiretroviral

273.e9 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY therapy of HIV-infected patients.92,93 Many of these drugs Corticosteroids have been associated with hypersensitivity responses ranging Allergic contact dermatitis due to topical application of cor- from mild cutaneous rashes to life-threatening SJS and ticosteroids is the most common type of allergic reaction TEN.94. Abacavir, a -analogue reverse transcrip- induced by this class of drugs. Very rarely, immediate-type tase inhibitor, causes severe hypersensitivity in 4% to 5% of allergic reactions to corticosteroids have been described. patients.95,96 Such reactions have been identified with a ge- Most such reported reactions are due to intravenous admin- netic risk factor, the presence of HLA B 5701.97,98 istration of and hydrocortisone106-111; however, and diluents have also been implicated. Medications for Autoimmune Diseases A variety of allergic reactions to disease-modifying antirheu- Heparin matic drugs (DMARDS) may occur, including , Hypersensitivity reactions to unfractionated heparin and low- D-penicillamine, sulfasalazine, , and le- molecular-weight heparin are uncommon and include throm- flunomide. Reactions such as vasculitis, DRESS, photoder- bocytopenia, various cutaneous eruptions, hypereosinophilia, matitis, and TEN have been reported with DMARDs. Newer and anaphylaxis. Mild thrombocytopenia is due to immunomodulator agents have been introduced for several aggregation and occurs in 1% to 3% of patients treated with autoimmune diseases. Although hypersensitivity reactions to unfractionated heparin. Severe thrombocytopenia is caused several of these have already occurred, it is too early to assess by immune complexes, a component of which is heparin- 112 the global impact of adverse events for diverse immunologic dependent IgG specific for platelet factor 4. This reaction interventions in early development. Allergic reactions to im- usually occurs after approximately 5 days of treatment with munosuppressant and anti-inflammatory drugs may be en- unfractionated heparin and is associated with development of countered in the treatment of chronic cutaneous diseases. and . A recent outbreak of anaphylactic Dermatologic immunosuppressant drugs, such as reactions to heparin in the United States and Germany was (eg, cyclosporine, , , and ), attributed to a contaminant in heparin lots, an oversulfated dapsone, and mycophenolate mofetil, have been reported to form of . This oversulfated chondroitin cause drug allergic reactions in addition to their known pre- sulfate contaminant has been shown in vitro and to dictable adverse reactions. cause activation of the kinin-kallikrein pathway with gener- ation of bradykinin, a potent vasoactive mediator, and C3a and C5a .113 Clinically, reactions to contami- Perioperative Agents and Blood Products nated heparin products were associated with and Anaphylactic and anaphylactoid reactions during general an- , and variably angioedema, but typically esthesia may be due to induction agents, neuromuscular lacked urticaria and pruritus.114 The findings of abdominal blocking agents, antibiotics, opiates, and . Because ana- pain and angioedema are somewhat analogous to C1 inhibitor phylactic reactions cannot be distinguished from anaphylac- deficiency in which symptoms are due to local production of toid, nonimmune occurrences, it has been recommended that bradykinin. plasma histamine, tryptase, and specific IgEs (if available) may be ordered at the time of reaction and skin tests be Local Anesthetics 99 performed later. Immediate generalized reactions to prota- Most adverse reactions to local anesthetics are not due to mine, including hypotension, , and , have been 100,101 IgE-mediated mechanisms but are due to nonallergic factors reported. Diabetic patients receiving protamine-contain- that include vasovagal responses, , toxic reactions ing insulins appear to be at 40 to 50 times greater risk for including dysrhythmias, and toxic or idiosyncratic reactions 102,103 developing anaphylaxis. Reactions due to blood and due to inadvertent intravenous effects. Documen- blood products include urticaria, anaphylaxis (particularly in tation of IgE-mediated reactions is extremely rare.115-118 patients with complete IgA deficiency), anaphylactoid reac- When there is concern about a previously reported reaction, tions, and transfusion-related acute injury (TRALI). skin testing and incremental challenge with a local TRALI is a complex syndrome that has multiorgan manifes- is a reasonable approach in the evaluation of a possible tations and has only recently been identified to be an important reaction. cause of transfusion-associated morbidity and mortality.104,105 Radiocontrast Media Opiates Anaphylactoid reactions occur in approximately 1% to 3% of Opiates and their analogs are a common cause of pseudoal- patients who receive ionic radiocontrast media (RCM) and lergic reactions that are generally mild, are not life-threaten- less than 0.5% of patients who receive nonionic agents.119,120 ing, and can be attenuated by preadministration of histamine1 Severe life-threatening reactions are less common, occurring receptor antihistamines. Skin test results to opiates are diffi- in 0.22% of patients receiving ionic RCM and 0.04% of cult to interpret because these agents cause release of hista- patients receiving nonionic agents.121 Risk factors for anaphy- mine from skin mast cells in all patients. lactoid reactions to RCM include female sex, asthma, and

VOLUME 105, OCTOBER, 2010 273.e10 a history of previous anaphylactoid reaction to RCM; asthma and rhinitis/sinusitis. A pharmacologic induction of ␤-blocker exposure and/or the presence of cardiovascular drug tolerance procedure (also known as aspirin desensitiza- conditions is associated with greater risk for more serious tion), during which tolerance to aspirin can be induced and anaphylactoid reaction.122-126 There is no convincing evidence maintained, is an important therapeutic option for patients in the medical literature that individuals with “seafood al- with AERD. lergy” are at elevated risk for anaphylactoid reaction to RCM A second clinical presentation of aspirin and NSAID drug compared with the general population. Management of a allergic reactions is an exacerbation of urticaria or angio- patient who requires RCM and has had a prior anaphylactoid in patients with chronic idiopathic urticaria. All drugs reaction to RCM includes the following: (1) determine that inhibit COX-1 cross-react to cause this reaction. Selec- whether the study is essential; (2) determine that the patient tive COX-2 inhibitors are generally well tolerated in patients understands the ; (3) ensure proper hydration; (4) use a with chronic idiopathic urticaria, although there may be rare nonionic, iso-osmolar RCM, especially in high-risk patients exceptions.142-144 A third type of drug allergic reaction is (asthmatic patients, patients taking ␤-blockers and those with aspirin or single NSAID-induced urticaria or angioedema or ); and (5) use a pretreatment regimen anaphylactic reaction, in which case other NSAIDs are tol- that has been documented to be successful in preventing most erated.145-148 A fourth type of drug allergic reaction to aspirin reactions.127-130 Delayed reactions to RCM, defined as those and NSAIDs is urticaria or angioedema due to aspirin and any occurring between 1 hour and 1 week after administration, NSAID that inhibits COX-1 in patients without chronic urti- occur in approximately 2% of patients.131 These reactions caria. These reactions may be either drug specific or cross- most commonly manifest as mild, self-limited cutaneous reactive to other NSAIDs.148 Rarely, some reactions to aspirin eruptions and do not require any treatment.131 The mechanism or NSAIDs do not fit precisely into these categories and may of delayed skin reactions to RCM appears to be have blended respiratory and cutaneous reactions. mediated.132 Allergic rashes are common adverse effects of , a thiopyridine inhibitor of platelet activation that is often Aspirin, NSAIDs, and Platelet Inhibitors recommended in aspirin-intolerant patients. Although the Aspirin and NSAIDs can cause a spectrum of drug allergic mechanisms of such reactions are unknown, successful oral reactions, including exacerbation of underlying respiratory induction of drug tolerance protocols have been reported. disease, urticaria, angioedema, anaphylaxis, and rarely pneu- monitis and . AERD is a clinical entity character- Angiotensin-Converting Enzyme Inhibitors ized by aspirin- and NSAID-induced respiratory reactions in patients with chronic rhinosinusitis and asthma. AERD does Angiotensin-converting enzyme (ACE) inhibitors have 2 ma- not fit precisely into a specific category of adverse drug jor adverse effects— and angioedema. Cough occurs in reactions. The mechanism of AERD is related to aberrant up to 20% of patients, is typically dry and nonproductive, and metabolism. Patients with AERD also have occurs more commonly in women, blacks, and Asians. The increased expression of the cysteinyl leuko- cough generally begins within the first few weeks of treat- triene 1 receptor and heightened responsiveness to inhaled ment, but occasionally the onset may occur much later. An- .133,134 Administration of aspirin leads to inhi- giotensin receptor blockers (ARBs) are not associated with bition of 1 (COX-1) with resultant decrease development of cough. The incidence of angioedema with ACE inhibitors is ap- in E2. normally inhibits 5-li- 149,150 poxygenase, but with a loss of this modifying effect, arachi- proximately 0.1% to 0.7% and appears to be more com- mon in blacks.151,152 The angioedema frequently involves the donic acid molecules are preferentially metabolized in the 153,154 5- pathway, resulting in increased production of or upper airway and can be life-threatening or fatal. Reports of angioedema of the intestinal tract secondary to cysteinyl . NSAIDs that preferentially inhibit 155 COX-2 but also inhibit COX-1 at higher doses may result in ACE inhibitors have also been described. Patients with C1 reactions, depending on the dose given. Selective COX-2 esterase inhibitor deficiency are at increased risk of more inhibitors almost never cause reactions in patients with frequent and severe episodes of angioedema with the admin- AERD and can typically be taken safely.135-139 istration of ACE inhibitors and should not receive these When patients with a history suggestive of AERD (ie, drugs. Patients typically take ACE inhibitors for months or asthma, rhinosinusitis, and history of respiratory reaction to even years before angioedema occurs. It is also puzzling that aspirin or aspirin-like drug) are challenged with aspirin, ap- recurrent episodes of angioedema occur sporadically despite proximately 85% will have a respiratory reaction confirming continued daily use of ACE inhibitors. Most patients with 140 angioedema related to ACE inhibitor usually tolerate the diagnosis. A recent study showed that 100% of patients 156 with a causing a severe reaction (poor ARBs. response to albuterol with need for medical intervention) had positive oral aspirin challenges.141 Management of patients Biologic Modifiers with AERD involves avoidance of aspirin and NSAIDs and In the past decade, a number of biologic agents have been aggressive medical and/or surgical treatment of underlying developed to neutralize proinflammatory cytokines, their cel-

273.e11 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Table 3. Classification of Adverse Reactions to Biologics imab (chimeric mouse-human IgG1 monoclonal Type of adverse reaction Example against the epidermal growth factor receptor), including IgE- mediated anaphylaxis, has been reported to occur at a na- High dose release syndrome tional rate of 3% or less but much higher (22%) in the Middle Hypersensitivity Delayed infusion reactions 183 Secondary Immunodeficiency Tuberculosis with anti-TNF South region of the United States. IgE antibodies in this SLE or vasculitis condition are specific for an oligosaccharide galactose- ␣-1, Atopic disorders 3-galactose, which is present on the Fab portion of the cetux- Cross-reactivity Acne from anti–epidermal imab heavy chain. In most of these patients, specific IgE growth factor receptor cetuximab antibodies were present in patients’ sera before Nonimmunologic adverse from therapy.184 Severe symptoms, such as fever, rigors, chills, and effects acute respiratory distress syndrome, may occur during admin- Abbreviations: SLE, systemic lupus erythematosus; TNF, tumor ne- istration of the first dose of certain monoclonal antibodies due crosis factor. to a cytokine release syndrome.185,186 Depending on the and type of reac- tion, readministration strategies may include medication pre- lular receptors, and IgE antibody.157,158 Because the clinical treatment, slowing infusion rates, or induction of drug toler- experience with these drugs varies (ie, phase 4 experiences), 184 the spectrum of reported allergic reactions may not yet be ance. In patients with immediate-type reactions, successful fully known for all of them. A separate type of classification induction of tolerance to , infliximab, and trastu- for adverse reactions to biological agents has been proposed zumab has been reported using a 6-hour protocol in combi- based on the mechanism of reactions (Table 3).159 High-dose nation with and premedication. reactions are related to high cytokine levels administered Rare anaphylactic reactions to anti-IgE humanized monoclo- directly or from cytokines released (cytokine release syn- nal antibody (omalizumab) were described during phase 3 clin- drome). Hypersensitivity reactions may be either antibody or ical trials and during the postmarketing surveillance period. The cell-mediated. Immune or cytokine dysregulation may result mechanism of these reactions is unclear. Many cases experi- in secondary immunodeficiency, autoimmunity, or allergic or enced either delayed-onset (2 hours) or protracted progression of atopic disorders. Cross-reactive reactions may occur when after dose administration. The Omalizumab the biologic agent is intended for a pathologic cell type but Joint Task Force report recommended that patients receiving cross-reacts with normal cells. Finally, biologics may also omalizumab should be directly observed, in a physician’s office, result in nonimmunologic adverse effects. after receiving omalizumab for 2 hours after the first 3 doses and Cytokines, including interferons and anti–tumor necrosis 30 minutes after subsequent doses.187 factor ␣ (TNF-␣) drugs, have been reported to cause a variety of drug allergic reactions. Allergic drug reactions ranging from cutaneous lesions to severe anaphylaxis may occur Complementary Medicines during treatment with recombinant interferons. A variety of The term complementary medicine includes herbal products, immune-mediated reactions have occurred during infliximab , minerals, amino , and essential oils.188 There is (Remicade) treatment for adult and juvenile rheumatoid ar- widespread belief that these products are safe because they thritis, Crohn’s disease and psoriasis. These reactions include are “natural.”189 However, well-recognized adverse effects, urticaria, flare-up of atopic dermatitis, maculopapular rashes, including anaphylaxis, have been reported in patients using leukocytoclastic vasculitis, serum sickness, and at least 7 products.190 Allergic reactions, including asthma instances of life-threatening anaphylactic reactions.160-173 and anaphylaxis, have been reported after of echi- Fewer adverse effects have been associated with nacea, an herb that is derived from several species of a (Humira), another recently available, fully humanized anti- flowering .191 A variety of cutaneous reactions and 1 TNF-␣ monoclonal antibody. These effects include injection instance of TEN have been reported after use of Chinese site pruritic rashes and new-onset asthma.174,175 New-onset herbal medications, which sometimes have been adulterated asthma may also appear during treatment with both inflix- with synthetic medications.192,193 Because the extent of this imab and (Enbrel). Immune-mediated reactions problem is unknown, patients should be questioned about the have also been rarely associated with the latter agent, a use of herbs and health supplements. recombinant TNF-␣ extracellular domain fused to human IgG1 Fc, which neutralizes soluble TNF-␣. These reactions include urticaria, rashes, injection site reactions, Other Agents leukocytoclastic vasculitis, lupus erythematosus, and 1 in- A number of other agents have been reported to cause drug stance of lung granulomatosis injury.176-182 allergic reactions, including N-, blue , vol- Both cutaneous and systemic allergic reactions have been ume expanders, iron-containing dextran, and preservatives. reported after treatment with both murine and humanized These reactions are discussed further in the text of the monoclonal antibodies. Hypersensitivity reactions to cetux- parameter.

VOLUME 105, OCTOBER, 2010 273.e12 ANNOTATIONS (FIGURE 1): description of the management of previous drug reactions and measures taken to prevent recurrence of such reactions. A ANNOTATION 1: Patient develops a possible adverse review of available medical records will help to confirm the drug reaction. patient’s medication history and may provide details about Adverse drug reactions encompass a wide range of clinical previously suspected drug reactions, including the treatment symptoms and signs that may be confused with a preexistent of these reactions. Host risk factors obtained from the history, disease, a proximate unexpected clinical event (eg, drug- such as age, sex, race, genetic associations (eg, atopy [usually induced disease vs viral hepatitis), or a disorder that for reactions to high-molecularϭweight biologicals], genetic would not have occurred if the drug had not been used (eg, polymorphisms of HLA-DR, and various drug metabolizing aseptic necrosis after glucocorticosteroids). As defined by the ), and presence of underlying disease (such as human World Health Organization, such reactions do not include immunodeficiency virus or systemic lupus erythematosus) therapeutic failures, intentional overdose, abuse of the drug, may support the possibility of a drug allergic reaction. or errors in administration. Adverse drug reactions occur Because adverse drug reactions may involve any organ more frequently in seriously ill patients requiring multiple system, a complete physical examination is recommended in drugs, human immunodeficiency virus–positive patients, or any patient who presents with a possible adverse reaction to patients with underlying hepatic or renal impairment. Occa- a drug. On the basis of the history and physical examination sionally, the occurrence of an unexpected event during drug findings, laboratory tests, including differential, blood tests, administration may be mistakenly attributed to extension of such as liver or renal function tests, a chest x-ray examina- the underlying disease rather than to the drug itself. In certain tion, and/or an electrocardiogram may be advisable. Specific instances, there may be an excessive reaction to the primary tests that may help to define immunopathogenesis are de- effect of the drug (eg, after a laxative). scribed in Annotations 5-11. In making a determination about whether the patient is experiencing an , the physician must ANNOTATION 3: Consider other possibilities. appreciate the wide scope of such reactions with special If review of , examination findings, and lab- emphasis on early recognition, pathophysiologic mecha- oratory test results do not indicate an adverse drug reaction, nisms, and severity. Predictable adverse drug reactions (type other causes should be considered. For example, chronic A) are usually dose dependent and related to the known urticaria, non–drug-related contact dermatitis, gastroenteritis, pharmacologic effects of the drug; examples include pharma- and viral exanthems are often mistaken for adverse drug cologic adverse effects and drug-drug interactions. Unpre- reactions. dictable reactions (type B) are elicited by relatively small doses and are usually unrelated to the pharmacologic actions ANNOTATION 4: Is drug-induced allergic reaction of the drug. suspected? In assessing the possibility of an adverse drug reaction, Once a suspected drug-induced reaction is confirmed, deter- knowledge about the dose, duration of use, temporal relation- mining whether this reaction is allergic in is an im- ship of drug administration, and predilection of individual portant next step. Drug allergy should be strongly suspected drugs to cause tissue or organ-specific adverse effects is when (1) the symptoms and physical findings are compatible important. In addition, the pharmacologic properties of drugs with an immune drug reaction; (2) there is (or was) a definite may provide useful clues about the type of adverse effects temporal relationship between administration of the drug and that is most likely to occur. Attention to these factors usually an ; (3) the class and/or structure of the drug can distinguish pseudoallergic reactions, which occur as a have been associated with immune reactions; (4) the patient result of mediator release from mast cells or basophils, from had previously received the drug (or a cross-reacting drug) on specific drug allergic reactions. 1 or more occasions; (5) there is no other clear cause for the presenting manifestations in a patient who is receiving med- ANNOTATION 2: Review of medical history, the ications known to cause hypersensitivity reactions; and (6) patient’s records, physical examination findings, and the skin tests and/or laboratory findings are compatible with clinical tests support an adverse drug reaction. drug hypersensitivity. A careful history, including a review of all available medical Involvement of the skin is often a prominent physical sign records, is essential. The history should include the follow- of drug allergy. The spectrum of drug-induced skin lesions ing: (1) timing of the onset, course, and duration of symp- includes urticaria, morbilliform rashes, papulovesicular and toms; (2) a description of symptoms with special attention to bullous eruptions, and exfoliative dermatitis. In addition to the organ system(s) involved; (3) the possible temporal rela- cutaneous manifestations, acute life-threatening anaphylactic tionship of symptoms with medication use; (4) a detailed list reactions also may involve the cardiorespiratory and gastro- and description of all medications, both prescription and intestinal systems. Allergic reactions to many drugs may nonprescription, that the patient is or was taking, including present with a wide array of abnormal physical findings dose, dosing interval, and length of treatment; (5) a detailed involving mucous membranes, lymph nodes, kidneys, liver, history of previously suspected drug reactions; and (6) a pleura, , joints, and other organs or tissues.

273.e13 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Typical examples of drug allergy corresponding to the ANNOTATION 7: Are appropriate confirmatory tests different types of Gell-Coombs reactions (using penicillin as available? an example) include (1) urticaria, laryngeal edema, and hy- Diagnosis of many cases of drug allergy is presumptive potension immediately after penicillin administration; (2) because specific confirmatory tests are usually not available. anemia in a patient receiving large doses of penicillin; (3) Useful clinical testing is predicated on the immunopathogen- fever, arthralgias, lymphadenopathy, and an urticarial rash 7 esis of the drug allergic reaction. The diagnostic potential of to 21 days after an injection of penicillin; and (4) maculo- percutaneous and intracutaneous tests in IgE-mediated al- papular eruption several days after initiation of penicillin lergy induced by large-molecular-weight biologicals is com- therapy. Patients’ presentations may not always be as typical parable to similar test reagents used in the diagnosis of as these examples. allergy. For low-molecular-weight biologicals, ade- quate data are not available to determine the predictive value of skin testing except for penicillin. Penicillin and a limited ANNOTATION 5: The adverse reaction is predictable number of other agents (eg, insulin) are the only agents for (eg, toxicity, , ) or due to which optimal negative predictive values for IgE-mediated idiosyncrasy, intolerance, or pseudoallergic effects of reactions have been established. Despite this lack of infor- the drug. mation about predictive values, testing for other agents may Most adverse drug reactions are predictable type A reac- provide useful information. tions. Examples of this type of reaction include acetamin- In situations where skin test results cannot be interpreted ophen-induced hepatic toxicity, sedation from antihista- properly (ie, generalized eczema, dermatographism, or lack mines, and interference of metabolism by of response to the positive histamine control) some in vitro . Clinical presentations of idiosyncratic and assays for specific IgE are available. However, they are not as intolerance reactions are often characteristic for certain sensitive as skin tests and generally do not have optimal drugs. Aspirin-induced tinnitus at therapeutic or subthera- negative predictive value. A diagnosis of anaphylaxis may be peutic doses is an example of drug intolerance. Hemolytic confirmed by an increase in plasma histamine, serum mature anemia induced by dapsone in patients with -6- tryptase (␤-tryptase), or 24-hour N-methylhistamine phosphate dehydrogenase deficiency is an example of drug (see Anaphylaxis Practice Parameter). idiosyncrasy. By contrast, pseudoallergic reactions are of- Immunopathogenesis of delayed drug reactions consistent ten symptomatically identical to IgE-mediated drug al- with type II (cytotoxic) or type III (serum sickness–like) lergy, may occur without a prior history of exposure, and according to the Gell-Coombs classification may be con- do not require prior sensitization. Pruritus after adminis- firmed by nonspecific and specific laboratory tests. Nonspe- tration of opiates is an example of a pseudoallergic reac- cific tests, such as a complete blood cell count, total eosino- tion. Some but not all nonimmunologic reactions can be phil and platelet counts, sedimentation rate or C-reactive confirmed by a graded challenge, including aspirin chal- protein, nuclear and/or cytoplasmic , comple- lenge in patients with possible aspirin-exacerbated respi- ment components (C3, C4), cryoglobulins, and/or a C1q ratory disease. binding assay may be appropriate. The results of specific tests, such as indirect and direct Coombs tests, are often positive in drug-induced hemolytic anemia, and specific tests ANNOTATION 6: Future management and prevention for immunocytotoxic thrombocytopenia and granulocytope- of nonimmune adverse drug reactions. nia are available in some medical centers. Dose modification may be possible in specific instances of Contact dermatitis (type IV Gell-Coombs reaction) may be toxicity, adverse effects, or drug interactions. In many cases, verified by drug-specific (eg, neomycin) epicutaneous patch use of the drug should be discontinued, and if available, a tests. Because sensitized T cells have been demonstrated in suitable alternative drug should be used. If the suspect drug is some delayed cutaneous reactions to oral drugs, patch tests to essential, gradually increasing doses of the drug may be those drugs may also be a helpful diagnostic adjunct. In oral administered by various graded challenge regimens in an antibiotic-induced delayed cutaneous reactions, drug-specific attempt to minimize adverse effects and to demonstrate proliferation and isolation of specific T-cell tolerance. clones can be demonstrated in some patients. However, the Cautious use of some agents inducing severe pseudoaller- predictive value of such patch testing and in vitro tests is gic reactions (eg, radiocontrast media) may be possible if unknown, and they are not available in most medical centers. patients are treated with premedication regimens consisting When laboratory tests are not diagnostic or available in of corticosteroids and antihistamines. Preventive measures non–IgE-mediated drug reactions, cautious provocative drug include education of the patient about the potential severity challenges under controlled conditions may be considered if and treatment of subsequent reactions, avoidance of the drug the risk of performing the challenge is thought to be less than and cross-reactive drugs, and personal use of Medic-Alert the risk of not using the drug. However, such drug challenges tags and/or bracelets are recommended. are generally contraindicated in cases of severe, life-threat-

VOLUME 105, OCTOBER, 2010 273.e14 ening immunocytotoxic reactions, such as vasculitic syn- Documented non–IgE-mediated reactions usually require dromes, exfoliative dermatitis, erythema multiforme major or prompt discontinuation of the drug therapy. If symptoms do Stevens-Johnson syndrome, toxic epidermal necrolysis, hep- not resolve spontaneously, additional symptomatic therapy atitis, hemolytic anemia, and nephritis. may be indicated. In the case of immune complex reactions, corticosteroids and antihistamines may be beneficial. In se- ANNOTATION 8: Are test results positive? vere cytotoxic or T-cell–mediated reactions, corticosteroids A positive immediate hypersensitivity skin test result using a may also be indicated. The use of glucocorticosteroids in nonirritating concentration of a drug suggests that the patient advanced stages of the erythema multiforme major or has specific IgE antibodies to the drug being tested and may Stevens-Johnson syndrome and TEN is controversial and be at significant risk for anaphylaxis or less severe immediate may increase the risk of infectious complications. hypersensitivity reactions, such as urticaria or angioedema. If the drug is determined to be the cause of the reaction, it The positive and negative predictive values of immediate should be avoided in the future and alternative drugs should hypersensitivity skin tests are unknown except for few be considered. If this is not possible, induction of drug agents. A positive skin test result to the major and/or minor tolerance (eg, desensitization) or graded challenge should be determinants of penicillin has a high predictive value of an considered. The prophylactic regimens before graded chal- immediate hypersensitivity reaction to penicillin. If the skin lenge or induction of drug tolerance may be necessary in test result is positive, there may be at least a 50% chance of some cases and are similar to those described in Annotation an immediate reaction to penicillin. Positive skin test results 4. Readministration of a drug(s) that caused certain severe to protein agents (eg, insulin, heterologous antisera, streptoki- non–IgE-mediated reactions (eg, Stevens-Johnson syndrome, nase) generally have good positive predictive value, although toxic epidermal necrolysis, Churg-Strauss syndrome, and ex- few large-scale, prospective studies to determine this index foliative dermatitis) is generally contraindicated with rare are available. Positive immediate hypersensitivity skin test exceptions, such as when the benefit of treatment of a life- results to nonirritating concentrations of nonpenicillin antibi- threatening illness outweighs the risk of a potentially life- otics may be interpreted as a presumptive risk of an imme- threatening reaction. diate reaction to such agents. Unfortunately, substantive data Every effort should be made to prevent allergic reactions to are limited on what constitutes a nonirritating concentration medications. Cross-reactivity between chemically related for many drugs. A positive in vitro specific IgE reaction to a drugs should be considered. Medications should be pre- drug or biological (eg, the major determinant of penicillin, scribed only for medically sound indications, and simulta- insulin, protamine) and tests also indi- neous use of multiple drugs should be avoided whenever cates significant risk for an immediate reaction, but a nega- possible. Orally administered drugs are less likely to produce tive test result lacks adequate sensitivity to exclude drug systemic reactions than drugs given topically or parenterally. allergy. As discussed in Annotation 7, various nonspecific For patients with a history of reactions to multiple antibiotics, and drug specific tests may help to confirm which immuno- antibiotics for presumptive diagnosis of respiratory tract in- pathogenic pathway is involved. fections should be avoided without further testing to confirm the necessity of therapy. Patients should be carefully instructed about avoiding the ANNOTATION 9: Diagnosis of drug hypersensitivity drug that caused the reaction or possible cross-reactive drugs. and immunologic reactions confirmed. Patients also need to be informed about agents that could be The diagnosis of drug hypersensitivity is confirmed by ap- present in over-the-counter preparations having trade names propriate specific or nonspecific skin and laboratory tests as that do not identify the drug. Emergency measures for the discussed in Annotations 5 and 6. Drug-specific tests are treatment of anaphylaxis, such as prompt use of self-admin- most useful for the diagnosis of Gell-Coombs types I and IV istered epinephrine, should be fully explained. In such situ- reactions and occasionally type II reactions. Various nonspe- ations, patients should not hesitate to call 911 or other emer- cific immunologic tests discussed in Annotation 5 may aid in gency help telephone numbers. MedicAlert jewelry is a the diagnosis of type III responses and atypical drug reac- useful way of alerting providers about previous drug reac- tions, with clinical manifestations suggesting mixed immu- tions, thereby preventing inadvertent readministration of the nopathogenetic mechanisms. It should be emphasized that drug. skin and in vitro tests for IgE-mediated reactions have no relationship to non-IgE immune-mediated reactions, such as ANNOTATION 11: Does test have high negative immune complex diseases, immunocytotoxic reactions, life- predictive value? threatening blistering syndromes, or vasculitic disorders. If an in vivo or an in vitro test result is negative for specific IgE antibodies directed against the drug, the likelihood that ANNOTATION 10: Management. the patient will tolerate the drug depends on the negative Acute anaphylactic reactions require immediate discontinua- predictive value of the test. The negative predictive value for tion of the drug therapy and prompt emergency measures, as insulin skin testing is good. The only antibiotic for which discussed in detail in the Anaphylaxis Practice Parameter.194 reliable negative predictive value has been determined is

273.e15 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY penicillin. The negative predictive value of commercial in Strength of recommendation: vitro tests for IgE-mediated penicillin allergy is inferior to A Directly based on category I evidence skin testing, and they do not test for minor determinants. B Directly based on category II evidence or extrapolated Tests for other small-molecular-weight drugs have unknown from category I evidence negative predictive values. Therefore, the likelihood of de- C Directly based on category III evidence or extrapolated veloping an IgE-mediated reaction cannot be ruled out by from category I or II evidence either skin or in vitro tests for such drugs. Valid negative D Directly based on category IV evidence or extrapolated predictive test values are not available for drugs that induce from category I, II, or III evidence cytotoxic or immune complex reactions. E Based on consensus of the Joint Task Force on Practice Parameters ANNOTATION 12: Patient not allergic to this drug. Within the limitations discussed in Annotations 7 and 8, a SUMMARY STATEMENTS OF THE EVIDENCE- negative test result for IgE-mediated, cytotoxic, immune BASED COMMENTARY complex, or contactant hypersensitivity suggests that the pa- I. INTRODUCTION tient is not allergic to the suspected drug and the drug may be Summary Statement 1: Adverse drug reactions (ADRs) are administered cautiously under observation. commonly encountered in both inpatient and outpatient set- tings and result in major health problems in the United States. (C) ANNOTATION 13: Patient may be allergic (despite negative drug-specific or nonspecific confirmatory test II. DEFINITIONS results). Summary Statement 2: ADRs are broadly categorized into Drug hypersensitivity cannot be confirmed by drug-specific predictable and unpredictable reactions. (D) tests in most cases because the positive and negative predic- Summary Statement 3: Unpredictable reactions are subdi- tive values have not been determined for most agents. More- vided into drug intolerance, drug idiosyncrasy, drug allergy, over, comparable data about the allergenicity of the parent and pseudoallergic reactions. (D) compound and its reactive end products or metabolites have Summary Statement 4: Drug intolerance is an undesirable pharmacologic effect that occurs at low and sometimes sub- only been determined for a few drugs, including penicillin. therapeutic doses of the drug without underlying abnormali- Because the general availability of tests for cytotoxic drug ties of metabolism, excretion, or bioavailability of the drug. reactions is limited, a determination of the causal relationship (D) of the drug can usually be made from the history, physical Summary Statement 5: Drug idiosyncrasy is an abnormal examination, and nonspecific tests. Similarly, only nonspe- and unexpected effect that is unrelated to the intended phar- cific laboratory tests can be used for the evaluation of drug- macologic action of a drug. (D) mediated immune complex disease. There are a number of Summary Statement 6: Drug allergy reactions are immu- drug reactions for which immunologic mechanisms are nologically mediated responses that result in the production strongly suspected but not yet been demonstrated. Thus, the of drug-specific antibodies, T cells, or both. (B) diagnosis of most allergic drug reactions is presumptive, Summary Statement 7: Manifestations of pseudoallergic based on the characteristic features of history, physical ex- reactions mimic IgE-mediated allergic reactions, but they are amination, and nonspecific laboratory adjunctive tests with- due to direct release of mediators from mast cells and ba- out definitive confirmation by positive drug-specific test sophils and do not require a preceding period of sensitization. results. (B) III. CLASSIFICATION OF IMMUNOLOGICALLY Classification of Recommendations and Evidence MEDIATED DRUG HYPERSENSITIVITY Category of evidence: REACTIONS Ia Evidence from meta-analysis of randomized controlled Summary Statement 8: Some drug allergic reactions may trials be classified by the Gell-Coombs classification paradigm of Ib Evidence from at least 1 randomized controlled trial hypersensitivity (type I: IgE mediated; type II: cytotoxic; type IIa Evidence from at least 1 controlled study without III: immune complex; type IV: cell mediated), whereas others randomization cannot be classified because of lack of knowledge of their IIb Evidence from at least 1 other type of quasiexperimen- immunopathogenesis or a mixed mechanism. (C) tal study Summary Statement 9: Allergic drug reactions may also be III Evidence from nonexperimental descriptive studies, classified according to the predominant organ system in- such as comparative studies volved (eg, cutaneous, hepatic, renal) or according to the IV Evidence from expert committee reports or opinions or temporal relationship to onset of symptoms (immediate, ac- clinical experience of respected authorities or both celerated, delayed). (D)

VOLUME 105, OCTOBER, 2010 273.e16 Summary Statement 10: To some extent, the structural cutaneous maculopapular eruptions due to oral antibiotics, characteristics of drugs may permit predictions about the type such as amoxicillin and sulfonamides. (C) of hypersensitivity reactions they are likely to cause. (C) Summary Statement 23: Patch testing at proper concentra- tions may be successful in detection of suspected contact A. IgE-Mediated Reactions (Gell-Coombs Type I) . (B) Summary Statement 11: IgE-mediated reactions may occur Summary Statement 24: After avoidance is instituted, top- after administration of a wide variety of drugs, biologicals, ical and/or systemic corticosteroids may be required for total and drug formulation agents, with the most common agents clearing of the dermatitis (provided that these drugs were not being antibiotics. (C) the primary causes). (C) B. Cytotoxic Reactions (Gell-Coombs Type II) E. Miscellaneous Syndromes Summary Statement 12: Cytotoxic reactions are very seri- Summary Statement 25: Some drugs or classes of drugs are ous and potentially life-threatening. (C) associated with characteristic syndromes that often do not Summary Statement 13: Immunohemolytic have ␣ conform to specific Gell-Coombs categories and sometimes occurred after treatment with quinidine, -, and are referred to as mixed drug reactions (ie, a mixture of penicillin. (C) immunologic mechanism). (C) Summary Statement 14: Positive direct and indirect Summary Statement 26: Many drugs, hematopoietic results in immunohemolytic anemia may reflect growth factors, cytokines, and interferons are associated with the presence of drug-specific IgG, complement, or an Rh vasculitis of skin and visceral organs. (C) determinant . (C) Summary Statement 27: The drug rash with eosinophilia Summary Statement 15: Immune-induced thrombocytope- and systemic symptoms (DRESS) syndrome is a drug-in- nia may result from treatment with heparin, quinidine, pro- duced, multiorgan inflammatory response that may be life- pylthiouracil, gold salts, sulfonamides, vancomycin, and threatening. First described in conjunction with anticonvul- other drugs. (C) Platelet membrane damage is mediated sant drug use, it has since been ascribed to a variety of drugs. mainly by drug–immune serum complexes, which are ad- (C) sorbed onto platelet membranes. (C) Summary Statement 28: Anticonvulsant hypersensitivity Summary Statement 16: Immune-mediated granulocytope- syndrome is mainly associated with aromatic anticonvulsant nia is uncommon but may be induced by cytotoxic antibodies drugs and is related to an inherited deficiency of epoxide synthesized in response to a variety of drugs. (C) hydrolase, an enzyme required for the metabolism of arene C. Immune Complex Reactions (Gell-Coombs Type III) oxide intermediates produced during hepatic metabolism. (B) Summary Statement 17: Immune complex (serum sickness) , , and are considered reactions were originally described with use of heterologous cross-reactive, but valproic acid, , and antisera, but they may also be caused by some small-molec- are therapeutic alternatives. (C) It is slower in onset than ular-weight drugs and monoclonal antibodies. (C) DRESS and presents with skin nodules, plaques, and lymph- Summary Statement 18: The chief manifestations of fever, adenopathy at times confused with lymphoreticular malignant rash, urticaria, lymphadenopathy, and arthralgias typically tumors (ie, pseudolymphoma). (B) appear 1 to 3 weeks after starting use of an offending agent. Summary Statement 29: Pulmonary manifestations of al- (C) lergic drug reactions include anaphylaxis, lupuslike reactions, Summary Statement 19: The for complete recov- alveolar or interstitial pneumonitis, noncardiogenic pulmo- ery from serum sickness is excellent; however, symptoms nary edema, and granulomatous vasculitis (ie, Churg-Strauss may last as long as several weeks. Treatment with systemic syndrome). Specific drugs are associated with different types of pulmonary reactions, such as bleomycin-induced fibrosis. corticosteroids and histamine1 receptor antihistamines may be required. (C) (C) Summary Statement 20: Drug-induced immune complex Summary Statement 30: Drug-induced lupus erythemato- disease may occur after exposure to heterologous sus (DILE) can have systemic forms and predominantly cu- (eg, thymoglobulin) or simple drugs (eg, penicillin, procain- taneous forms. Procainamide and hydralazine are the most , phenylpropanolamine). (C) frequently implicated drugs for systemic DILE, and antihis- tone antibodies are present in more than 90% of patients but D. Cell-Mediated Reactions (Gell-Coombs Type IV) occur less commonly with minocycline, propylthiouracil, and Summary Statement 21: Contact dermatitis produced by . (C) topical drugs (such as , neomycin, glucocorticoste- Summary Statement 31: Drugs most commonly associated roids, local anesthetics, and antihistamines) and/or excipients with cutaneous DILE include hydrochlorothiazide, calcium contained in topical formulations are due to cell-mediated channel blockers, angiotensin-converting enzyme inhibitors, reactions. (C) and systemic agents. Anti-Ro and anti-SSA anti- Summary Statement 22: It is postulated that Gell-Coombs bodies are usually present, whereas antihistone antibodies are type IV reactions are also responsible for some delayed much less frequent. (C)

273.e17 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Summary Statement 32: The recognition of immunologi- IV. RISK FACTORS cally mediated, drug-induced granulomatous disease with or Summary Statement 46: The most important risk factors for without vasculitis has increased in recent years. (C) drug hypersensitivity may be related to the chemical property Summary Statement 33: Immunologic hepatitis may occur and molecular weight of drugs. (C) after sensitization to para-aminosalicylic acid, sulfonamides, Summary Statement 47: Other drug-specific risk factors for and phenothiazines. (C) drug hypersensitivity include the dose, route of administra- Summary Statement 34: Erythema multiforme minor is a tion, duration of treatment, repetitive exposure to the drug, cell-mediated hypersensitivity reaction associated with vi- and concurrent illnesses (eg, Epstein-Barr virus and ruses, other infectious agents, and drugs. It manifests as amoxicillin rash). (C) pleomorphic cutaneous eruptions, with target lesions being Summary Statement 48: Host risk factors for drug hyper- most characteristic. (C) sensitivity include age, sex, atopy, underlying diseases (such Summary Statement 35: There is no consensus on the as lupus erythematous and human immunodeficiency virus), distinction between erythema multiforme major and Stevens- and specific genetic polymorphisms. (C) Johnson syndrome. These disorders involve mucosal surfaces V. CLINICAL EVALUATION AND DIAGNOSIS OF as well as the skin. (D) DRUG ALLERGY Summary Statement 36: Use of systemic corticosteroids for Summary Statement 49: The history should focus on pre- treatment of erythema multiforme major or Stevens-Johnson vious and current drug use and the temporal sequence of syndrome is controversial. (D) events between initiation of therapy and onset of symptoms. Summary Statement 37: Toxic epidermal necrolysis (ie, (C) Lyell syndrome) is distinguished from Stevens-Johnson syn- Summary Statement 50: Physical examination should in- drome by the extent of epidermal detachment. (D) clude all systems that could possibly account for the clinical Summary Statement 38: Systemic corticosteroids are asso- presentation. (C) ciated with increased mortality when used for the manage- Summary Statement 51: Cutaneous manifestations are the ment of advanced toxic epidermal necrolysis (C). Treatment most common presentation for drug allergic reactions. Char- with high-dose intravenous immunoglobulin is controversial. acterization of cutaneous lesions is important in regard to (D) determining the cause, further diagnostic tests, and manage- Summary Statement 39: Toxic epidermal necrolysis should ment decisions. (C) Summary Statement 52: Numerous cutaneous reaction pat- be managed in a unit. (D) terns have been reported in drug allergy, including exan- Summary Statement 40: Serum sickness–like reactions thems, urticaria, angioedema, acne, bullous eruptions, fixed caused by cephalosporins (especially cefaclor) usually are drug eruptions, erythema multiforme, lupus erythematosus, due to altered metabolism of the drug, resulting in reactive photosensitivity, psoriasis, purpura, vasculitis, pruritus, and intermediates. (B) life-threatening cutaneous reactions, such as Stevens-Johnson Summary Statement 41: Immunologically mediated ne- syndrome, toxic epidermal necrolysis, exfoliative dermatitis, phropathies may present as interstitial nephritis (such as with and drug rash with eosinophilia and systemic symptoms ) or as membranous glomerulonephritis (eg, gold, (DRESS). (C) penicillamine, and allopurinol). (C) Summary Statement 53: Possible laboratory tests might F. Other Classification Systems for Drug Allergy include but are not limited to a chest x-ray examination, electrocardiography, a complete blood cell count with differ- Summary Statement 42: In addition to Gell-Coombs hy- ential, sedimentation rate or C-reactive protein, autoantibody persensitivity reactions, there are a number of other mecha- tests, and specific immunologic tests. (C) nistic and clinical classifications for drug allergy. (C) Summary Statement 54: The most useful test for detecting Summary Statement 43: The p-i concept (pharmacologic IgE-mediated drug reactions caused by penicillin and many interaction with immune receptors) is a recently proposed large-molecular-weight biologicals is immediate hypersensi- addition to drug hypersensitivity classification in which a tivity skin testing. (B) drug binds noncovalently to a T-cell receptor, which may Summary Statement 55: Specialized immunologic tests are lead to an immune response via interaction with a major sometimes able to confirm the immunologic basis of drug- histocompatibility complex receptor. (C) induced cytotoxic reactions. (B) Summary Statement 44: From a clinical standpoint, the Summary Statement 56: Drug patch testing may be useful most practical method of classifying drug reactions is by for certain types of cutaneous drug reactions, including mac- predilection for various tissue and organ systems. (D) ulopapular exanthems, acute generalized exanthematous pus- Summary Statement 45: The structural characteristics of tulosis, and fixed drug eruptions, but generally is not helpful drugs and biological products may permit predictions about for Stevens-Johnson syndrome or urticarial eruptions. The what type of hypersensitivity reactions to expect from certain lack of standardization of reagent concentrations may limit classes of therapeutic substances. (C) the clinical usefulness of drug patch testing. (B)

VOLUME 105, OCTOBER, 2010 273.e18 Summary Statement 57: Lymphocyte proliferation assays Stevens-Johnson syndrome or toxic epidermal necrolysis. may have utility as retrospective indicators of cell-mediated One example of when the benefit of treatment may outweigh drug reactions, but their positive and negative predictive the risk of reaction is imatinib for treatment of malignant values have not been determined and they are not available in tumors. (C) most medical centers. (C) Summary Statement 68: Pharmacologic induction of drug Summary Statement 58: In complex cases where multiple tolerance to aspirin (eg, aspirin desensitization) is primarily drugs are involved without a clear-cut temporal relationship, intended for patients with AERD, and unlike other types of a skin biopsy may be useful in suggesting a drug-induced desensitization, its purpose is to cautiously induce (rather eruption. However, there are no absolute histologic criteria than prevent) a reaction, after which patients become toler- for the diagnosis of drug-induced eruptions, and a skin biopsy of aspirin and nonsteroidal anti-inflammatory drugs may not definitively exclude alternative causes. (C) (NSAIDs). (B) VI. MANAGEMENT AND PREVENTION OF DRUG Summary Statement 69: Some induction of drug tolerance ALLERGIC REACTIONS procedures have been described that appear to be successful Summary Statement 59: Ideally ADRs should be pre- through currently undefined mechanisms. (C) vented. Steps to prevent allergic drug reactions include (1) a Summary Statement 70: The objective of a graded chal- careful history to determine host risk factors, (2) avoidance of lenge is to cautiously introduce a drug in patients who are cross-reactive drugs, (3) use of predictive tests when avail- unlikely to be allergic to it. Unlike induction of drug toler- able, (4) proper and prudent prescribing of drugs (especially ance, it does not modify patients’ response to a drug. (D) antibiotics) that are frequently associated with adverse reac- VII. SPECIFIC DRUGS tions, (5) use of oral drugs when possible, and (6) documen- A. ␤-Lactam Antibiotics tation of ADR in the patient’s . (D) 1. Penicillin Summary Statement 60: For some allergic drug reactions, Summary Statement 71: Approximately 10% of patients withdrawal of the drug may be all that is required for treat- report a history of penicillin allergy, but after complete eval- ment. (C) uation, up to 90% of these individuals are able to tolerate Summary Statement 61: Anaphylactic drug reactions re- . (B) quire prompt emergency treatment as discussed extensively Summary Statement 72: Treatment of patients assumed to in “The Diagnosis and Management of Anaphylaxis: An be penicillin allergic with alternate broad-spectrum antibiot- Updated Practice Parameter.” (B) ics may compromise optimal medical care by leading to Summary Statement 62: Glucocorticosteroids may be re- multiple drug-resistant organisms, higher costs, and increased quired for immune complex reactions, drug-induced hemato- logic diseases, early stages of erythema multiforme major/ toxic effects. (C) Stevens-Johnson syndrome, and contact sensitivities. (C) Summary Statement 73: Evaluation of patients with peni- Summary Statement 63: What has often been referred to as cillin allergy by skin testing leads to reduction in the use of drug desensitization is more appropriately described in this broad-spectrum antibiotics and may decrease costs. (B) parameter as a temporary induction of drug tolerance. (D) Summary Statement 74: The rate of penicillin-induced Summary Statement 64: Induction of drug tolerance mod- anaphylaxis after parenteral administration is approximately ifies a patient’s response to a drug to temporarily allow 1 to 2 per 10,000 treated patients. (C) treatment with it safely. It is only indicated in situations Summary Statement 75: Penicillin is immunologically inert where an alternate non–cross-reacting medication cannot be and haptenates proteins after undergoing spontaneous con- used. (B) version under physiologic conditions to reactive intermedi- Summary Statement 65: Through various mechanisms, in- ates. These transformation products are known as penicillin duction of drug tolerance procedures induces a temporary major and minor antigenic determinants. (C) state of tolerance to the drug that is maintained only as long Summary Statement 76: Penicillin skin testing is the most as the patient continues to take the specific drug. (B) reliable method for evaluating IgE-mediated penicillin al- Summary Statement 66: Immunologic IgE induction of lergy. (B) Ideally, penicillin skin testing should be performed drug tolerance (drug desensitization) is the progressive ad- with both major and minor determinants. The negative pre- ministration of an allergenic substance to render effector cells dictive value of penicillin skin testing for immediate reactions less reactive. These procedures typically are performed approaches 100%, whereas the positive predictive value is within hours, and the typical starting dose is in the microgram between 40% and 100%. (B) range. (B) Summary Statement 77: Skin testing with the major deter- Summary Statement 67: For some delayed non–IgE-medi- minant and penicillin G only (without penicilloate or pe- ated cutaneous reactions, immunologic non-IgE induction of nilloate) may miss up to 20% of allergic patients, but data on drug tolerance may be performed to allow treatment with the this are conflicting. (C) drug. However, it is generally contraindicated, with rare Summary Statement 78: Penicillin G left in solution exceptions, for serious non–IgE-mediated reactions, such as (“aged” penicillin) does not spontaneously degrade to form

273.e19 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY antigenic determinants and has no role in penicillin skin penicillin determinants) and are able to tolerate other peni- testing. (B) cillin class compounds. (C) Summary Statement 79: Penicillin skin testing without the Summary Statement 91: Amoxicillin and ampicillin are major determinant is not recommended because this would associated with the development of a delayed maculopapular fail to identify many patients with penicillin specific IgE rash in approximately 5% to 10% of patients. (C) These antibodies. (B) reactions are not related to IgE-mediated allergy, and they are Summary Statement 80: When performed by skilled per- postulated in many cases to require the presence of a concur- sonnel using proper technique, serious reactions due to pen- rent viral infection or another underlying illness. (D) icillin skin testing are extremely rare. (C) 3. Cephalosporins Summary Statement 81: Penicillin skin testing may be Summary Statement 92: The overall reaction rate to ceph- performed electively—when patients are well and not in alosporins is approximately 10-fold lower than it is for pen- immediate need of antibiotic therapy. Alternatively, penicillin icillin. (C) skin testing may be performed when treatment with a peni- Summary Statement 93: Most hypersensitivity reactions to cillin compound is contemplated. (D) cephalosporins are probably directed at the R-group side Summary Statement 82: Patients who have had negative chains rather than the core ␤-lactam portion of the molecule. skin test results to penicillin major and minor determinants (D) may receive penicillin with minimal risk of an IgE-mediated Summary Statement 94: Skin testing with native cephalo- reaction. Depending on the reaction history, the first dose sporins is not standardized, but a positive skin test result may need to be given via graded challenge. (D) using a nonirritating concentration suggests the presence of Summary Statement 83: Penicillin skin test–positive pa- drug specific IgE antibodies. (D) A negative skin test result tients should avoid penicillin, but if they develop an absolute does not rule out an allergy because the negative predictive need for penicillin, rapid induction of drug tolerance may be value is unknown. (D) performed. (B) Summary Statement 95: Patients with a history of an im- Summary Statement 84: Resensitization after treatment mediate-type reaction to 1 cephalosporin should avoid ceph- with oral penicillin is rare, and therefore penicillin skin alosporins with similar R-group side chains. (D) Treatment testing does not routinely need to be repeated in patients with with cephalosporins with dissimilar side chains may be con- a history of penicillin allergy who have tolerated 1 or more sidered, but the first dose should be given via graded chal- courses of oral penicillin. (B) lenge or induction of drug tolerance, depending on the sever- Summary Statement 85: Resensitization after treatment ity of the previous reaction. (D) with parenteral penicillin appears to be higher than for oral Summary Statement 96: Cephalosporins and penicillins treatment, and therefore repeat penicillin skin testing may be share a common ␤-lactam ring structure and moderate cross- considered in patients with a history of penicillin allergy who reactivity has been documented in vitro. (B) have tolerated a course of parenteral penicillin. (C) Summary Statement 86: The negative predictive value of 4. Cephalosporin administration to patients with a penicillin skin testing without penicilloylpolylysine is poor history of penicillin allergy because many allergic patients show skin test reactivity only Summary Statement 97: Since 1980, studies show that to the major determinant. (B) approximately 2% of penicillin skin test–positive patients Summary Statement 87: When penicillin skin testing is react to treatment with cephalosporins, but some of these unavailable, evaluation of penicillin allergy is based on the reactions may be anaphylactic reactions. (C) reaction history and likelihood of needing treatment with Summary Statement 98: Without preceding penicillin skin penicillins. (C) testing, cephalosporin treatment of patients with a history of Summary Statement 88: Patients with a vague and/or dis- penicillin allergy, selecting out those with severe reaction tant history of penicillin allergy may be candidates to receive histories, show a reaction rate of 0.1% based on recent penicillins via graded challenge. Patients with recent or con- studies. (C) vincing reaction histories should only receive penicillins via Summary Statement 99: Penicillin skin testing, when avail- rapid induction of drug tolerance. (C) able, should be considered before administration of cephalo- Summary Statement 89: The usefulness of in vitro tests for sporins in patients with a history of penicillin allergy. (E) penicillin specific IgE is limited by their uncertain predictive Summary Statement 100: Patients who have a history of a value. They are not suitable substitutes for penicillin skin possible IgE-mediated reaction to penicillin, regardless of the testing. (C) severity of the reaction, may receive cephalosporins with minimal concern about an immediate reaction if skin test 2. Ampicillin and amoxicillin results for penicillin major and minor determinants are neg- Summary Statement 90: Some patients with immediate- ative. (B) type reactions to amoxicillin and ampicillin have IgE anti- Summary Statement 101: Treatment options for penicillin bodies directed at the R-group side chain (rather than the core skin test–positive patients include (1) administration of an

VOLUME 105, OCTOBER, 2010 273.e20 alternate (non–␤-lactam) antibiotic, (2) administration of antibiotics. (C) Evaluation of possible allergy to these anti- cephalosporin via graded challenge, or (3) administration of biotics should be limited to situations when treatment with cephalosporin via rapid induction of drug tolerance. (E) the drug is anticipated (rather than electively as for penicil- Summary Statement 102: Skin testing to the cephalosporin lin). (D) followed by graded challenge appears to be a safe method for Summary Statement 111: Skin testing with nonirritating administration of some cephalosporins in penicillin allergic concentrations of non–␤-lactam antibiotics is not standard- patients. (B) ized. A negative skin test result does not rule out the possi- Summary Statement 103: If penicillin and cephalosporin bility of an immediate-type allergy. A positive skin test result skin testing is unavailable, depending on the reaction history, suggests the presence of drug specific IgE antibodies, but the cephalosporins may need to be given via graded challenge or predictive value is unknown. (D) rapid induction of drug tolerance. (E) Summary Statement 112: Patients with a history of reac- tions to non–␤-lactam antibiotics consistent with an IgE- 5. Penicillin administration to patients with a history of mediated mechanism should only receive them if an alternate cephalosporin allergy agent cannot be substituted and only via rapid induction of Summary Statement 104: Patients allergic to amoxicillin drug tolerance. (D) should avoid cephalosporins with identical R-group side Summary Statement 113: Sulfonamide antibiotics rarely chains (, cefprozil, ) or receive them via cause IgE-mediated reactions and more commonly result in rapid induction of drug tolerance. (C) Similarly, patients delayed maculopapular rashes, particularly in human immu- allergic to ampicillin should avoid cephalosporins and carba- nodeficiency virus–positive patients. (C) with identical R-group side chains (cephalexin, ce- Summary Statement 114: There is no evidence to suggest faclor, cephradine, cephaloglycin, ) or receive them allergic cross-reactivity between sulfonamide antibiotics and via rapid induction of drug tolerance. (C) nonantibiotic sulfonamides. (C) Summary Statement 105: Patients with a history of an Summary Statement 115: Vancomycin rarely causes IgE- immediate-type reaction to a cephalosporin should undergo mediated reactions, but more than 50% of patients experience penicillin skin testing, if available, before treatment with immediate cutaneous erythema, flushing, and pruritus (red penicillin. (E) If test results are negative, they may safely man syndrome), which is the result of non–IgE-mediated receive penicillins. (B) If test results are positive, an alternate histamine release. (C) drug should be used or they should undergo rapid penicillin Summary Statement 116: Red man syndrome reactions can induction of drug tolerance. (B) If penicillin skin testing is be prevented by slowing the rate of infusion and premedicat- unavailable, penicillin may be administered via cautious ing with histamine receptor antihistamines. (C) graded challenge. (C) 1 Summary Statement 117: rarely cause 6. Monobactams (aztreonam) drug allergic reactions, including IgE-mediated systemic re- Summary Statement 106: Aztreonam is less immunogenic actions. (C) than penicillin and cephalosporins, and clinical allergic reac- Summary Statement 118: IgE-mediated and non–IgE-me- tions to aztreonam are less common than other ␤-lactam diated anaphylactic reactions have been reported with quin- antibiotics. (C) olones. In vitro studies suggest a large extent of allergic Summary Statement 107: Aztreonam does not cross-react cross-reactivity among quinolones, but there are no clinical with other ␤-lactams except for , with which it studies to confirm this. (C) shares an identical R-group side chain. (B) Summary Statement 119: Anaphylactic or anaphylactoid reactions during the operative and perioperative periods may 7. Carbapenems be caused by induction agents, muscle-relaxing agents, opi- Summary Statement 108: Limited data indicate lack of ates, antibiotics, and . (C) significant allergic cross-reactivity between penicillin and carbapenems. (B) Penicillin skin test–negative patients may C. Antimycobacterial Drugs safely receive carbapenems. (C) Penicillin skin test–positive Summary Statement 120: Allergic drug reactions to anti- patients and patients with a history of penicillin allergy who mycobacterial drugs present significant problems in the im- do not undergo skin testing should receive carbapenems via plementation of long-term treatment regimens and preventing graded challenge. (C) to tuberculosis. (C) B. Non–␤-Lactam Antibiotics D. Diabetes Medications Summary Statement 109: Any non–␤-lactam antibiotic has Summary Statement 121: The advent of human recombi- the potential of causing an IgE-mediated reaction, but these nant insulin has greatly reduced the incidence of life-threat- appear to occur less commonly than with ␤-lactam antibiot- ening allergic reactions to approximately 1%. (C) ics. (C) Summary Statement 122: Metformin and sulfonylurea Summary Statement 110: There are no validated diagnostic antidiabetic drugs rarely cause immune-mediated reactions, tests for evaluation of IgE-mediated allergy to non–␤-lactam such as leukocytoclastic vasculitis, generalized arteritis, gran-

273.e21 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY ulomatous hepatitis, and autoimmune . G. Disease-Modifying Antirheumatic Drugs (DMARDS) (C) Summary Statement 133: Apart from adverse reactions to aspirin, other NSAIDs, and certain derivatives E. Cancer Chemotherapeutics (discussed in VII-R), a variety of allergic reactions to other Summary Statement 123: Cancer chemotherapeutic agents, DMARDs may occur. (C) such as (paclitaxel, docetaxel), platinum compounds (cisplatin, carboplatin, oxaliplatin), and , may H. Modifying Drugs for Dermatologic Diseases cause severe immediate-type reactions, which may be either Summary Statement 134: Although hypersensitivity reac- anaphylactic or anaphylactoid in nature. (C) tions to several unique therapeutic agents for autoimmune Summary Statement 124: For some chemotherapeutics diseases have already occurred, it is too early to assess the (primarily the platinum-based compounds), skin testing may global impact of adverse events for diverse immunologic assist in identifying allergic patients who are at increased risk interventions in early development. (C) for an allergic reaction and for confirming IgE-mediated I. Immunomodulatory Agents for Autoimmune Diseases sensitivity. (C) Summary Statement 135: Allergic reactions to immunosup- Summary Statement 125: Rapid induction of drug tolerance pressant and anti-inflammatory drugs are commonly encoun- protocols are available for most chemotherapeutic agents that tered in the treatment of chronic cutaneous diseases. (C) cause immediate-type reactions, but they are not uniformly successful. (C) J. Perioperative Agents Summary Statement 136: Summary Statement 126: Methotrexate can cause intersti- Anaphylactic or anaphylactoid reactions during the operative and perioperative periods may tial reactions in the lungs, which can progress to fibrosis if be caused by induction agents, muscle-relaxing agents, opi- use of the drug is continued. (C) ates, antibiotics, and latex allergy. (C) F. Human Immunodeficiency Virus (HIV) Medications K. Blood and Blood Products Summary Statement 127: Patients infected with HIV have Summary Statement 137: Reactions due to blood and blood an increased frequency of adverse reactions to a variety of products include urticaria, anaphylaxis (particularly in pa- drugs, and the pathogenesis of these reactions is likely mul- tients with complete IgA deficiency), anaphylactoid reac- tifactorial. (C) tions, and transfusion-related acute lung injury (TRALI). (C) Summary Statement 128: The most common ADR in HIV- positive patients who take trimethoprim-sulfamethoxazole is L. Opiates a morbilliform and/or maculopapular eruption, often associ- Summary Statement 138: Opiates and their analogs are a ated with fever that occurs after 7 to 12 days of therapy. (C) common cause of pseudoallergic reactions that are generally Summary Statement 129: HIV-positive patients who have mild, are not life-threatening, and can be attenuated by pread- experienced typical delayed exanthematous reactions to tri- ministration of histamine1 receptor antihistamines. (C) methoprim-sulfamethoxazole and who require treatment with M. Corticosteroids the drug (such as for Pneumocystis carinii pneumonia) may Summary Statement 139: Immediate-type reactions to cor- undergo one of several published trimethoprim-sulfamethox- ticosteroids are rare and may be either anaphylactic or ana- azole induction of drug tolerance protocols. (D) Usually, this phylactoid in nature. (C) should be done after waiting for at least 1 month after the Summary Statement 140: Most reported reactions to corti- reaction to increase the likelihood of success. (D) costeroids involved intravenous methylprednisolone and hy- Summary Statement 130: Reintroduction of trimethoprim- drocortisone, and preservatives and diluents have also been sulfamethoxazole in HIV-positive patients with a history of implicated. (C) more severe reactions to trimethoprim-sulfamethoxazole, such as Stevens-Johnson syndrome or toxic epidermal N. Protamine Summary Statement 141: necrolysis, is generally contraindicated, with rare exceptions, Severe immediate reactions may occur in patients receiving protamine for reversal of - such as treatment of a life-threatening infection, in which rinization. (C) case the benefit of treatment outweighs the risk of a poten- Summary Statement 142: Diabetic patients receiving pro- tially life-threatening reaction. (D) tamine-containing insulin are at greatest risk of severe reac- Summary Statement 131: Antiretroviral drugs used for tions due to intravenous protamine. (C) highly active antiretroviral therapy (HAART) of HIV-in- fected patients may cause allergic reactions of various kinds. O. Heparin (C) Summary Statement 143: Hypersensitivity reactions to un- Summary Statement 132: Abacavir is the most common fractionated heparin and low-molecular-weight heparin are HAART drug to cause severe allergic reactions, and this risk uncommon and include thrombocytopenia, various cutaneous is associated with the presence of HLA B 5701. (C) eruptions, hypereosinophilia, and anaphylaxis. (C)

VOLUME 105, OCTOBER, 2010 273.e22 P. Local Anesthetics Summary Statement 154: Aspirin and NSAIDs that inhibit Summary Statement 144: Most adverse reactions to local cyclooxygenase 1 (COX-1) cross-react and cause respiratory anesthetics are not due to IgE-mediated mechanisms but are reactions in AERD, whereas selective COX-2 inhibitors al- due to nonallergic factors that include vasovagal responses, most never cause reactions in patients with AERD and can anxiety, toxic reactions including dysrhythmias, and toxic or typically be taken safely. (B) idiosyncratic reactions due to inadvertent intravenous epi- Summary Statement 155: Aspirin desensitization followed nephrine effects. (C) by daily aspirin therapy to perpetuate the aspirin tolerant state Summary Statement 145: To exclude the rare possibility of in patients with AERD is indicated in patients with AERD if an IgE-mediated reaction to local anesthetics, skin testing and aspirin or NSAIDs are therapeutically necessary for treatment graded challenge can be performed in patients who present of some other condition, such as cardiac or rheumatologic with a reaction history suggestive of possible IgE-mediated diseases. (D) allergy to these drugs. (B) Summary Statement 156: Aspirin desensitization followed by daily aspirin has been associated with improved outcomes Q. Radiocontrast Media (RCM) in patients with AERD who are poorly controlled with med- Summary Statement 146: Anaphylactoid reactions occur in ical and/or surgical management. (D) approximately 1% to 3% of patients who receive ionic RCM Summary Statement 157: A second reaction type to aspirin and less than 0.5% of patients who receive nonionic RCM. and NSAIDs is exacerbation of urticaria and angioedema in (C) approximately 20% to 40% of patients with underlying Summary Statement 147: Risk factors for anaphylactoid chronic idiopathic urticaria. (C) Drugs that inhibit COX-1 reactions to RCM include female sex, atopy, concomitant use cross-react to cause this reaction, whereas selective COX-2 ␤ of -blocking drugs, and a history of previous reactions to inhibitors typically are better tolerated by these patients. (C) RCM. (C) Summary Statement 158: A third reaction type to aspirin Summary Statement 148: Although asthma is associated and NSAIDs is suggestive of an IgE-mediated mechanism with an increased risk of a RCM reaction, specific sensitivity and manifests as urticaria or angioedema or anaphylaxis, and to seafood (which is mediated by IgE directed to proteins) it occurs in patients with no underlying respiratory or cuta- does not further increase this risk. There is no evidence that neous disease. (C) These reactions appear to be drug specific, sensitivity to iodine predisposes patients to RCM reactions. and there is no cross-reactivity with other NSAIDs. (D) (C) Summary Statement 159: A fourth reaction type to aspirin Summary Statement 149: Patients who experienced previ- and NSAIDs is urticaria or angioedema caused by all drugs ous anaphylactoid reactions to RCM should receive nonionic, that inhibit COX-1, and it occurs in patients without a prior iso-osmolar agents and be treated with a premedication reg- history of chronic urticaria. (C) imen, including systemic corticosteroids and histamine1 re- Summary Statement 160: Rarely, patients exhibit com- ceptor antihistamines; this will significantly reduce, but not bined (“blended”) respiratory and cutaneous reaction to as- eliminate, the risk of anaphylactoid reaction with re-exposure pirin or NSAIDs and hence cannot be classified into 1 of the to contrast material. (D) 4 reaction types described above. (C) Summary Statement 150: Delayed reactions to RCM, de- fined as reactions occurring 1 hour to 1 week after adminis- S. Angiotensin-Converting Enzyme (ACE) Inhibitors tration, occur in approximately 2% patients. (C) Most are Summary Statement 161: ACE inhibitors are associated mild, self-limited cutaneous eruptions that appear to be T-cell with 2 major adverse effects—cough and angioedema. (C) mediated, although more serious reactions, such as Stevens- Summary Statement 162: ACE inhibitor–related cough of- Johnson syndrome, toxic epidermal necrolysis, and DRESS ten begins within the first few weeks of treatment and occurs syndrome have been described. in up to 20% of patients, particularly women, blacks, and Asians. (C) R. Aspirin and Nonsteroidal Anti-inflammatory Drugs Summary Statement 163: The mechanism of ACE inhibi- (NSAIDs) tor–related cough is unclear. The cough resolves with discon- Summary Statement 151: One type of adverse reaction to tinuation of the drug therapy in days to weeks. (D) aspirin/NSAIDs is AERD, a clinical entity characterized by Summary Statement 164: Patients with ACE inhibitor– aspirin- and NSAID-induced respiratory reactions in patients related cough are able to tolerate angiotensin receptor block- with underlying asthma and/or rhinitis or sinusitis. (B) ers (ARBs). (A) Summary Statement 152: The mechanism of AERD ap- Summary Statement 165: ACE inhibitor–induced angio- pears to be related to aberrant arachidonic acid metabolism. edema occurs in approximately 0.1% to 0.7% of patients and (B) is most common in blacks. (C) Summary Statement 153: Controlled oral provocation with Summary Statement 166: ACE inhibitor–induced angio- aspirin is considered to be the most conclusive way to con- edema frequently involves the face and oropharynx and can firm the diagnosis of AERD. (B) be life-threatening or fatal. (C)

273.e23 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Summary Statement 167: The mechanism of ACE inhibi- EVIDENCE-BASED COMMENTARY tor–induced angioedema may be related to interference with I. INTRODUCTION bradykinin degradation. It may take months or years after Summary Statement 1: Adverse drug reactions (ADRs) are initiation of therapy for a reaction to appear and often occurs commonly encountered in both inpatient and outpatient set- sporadically despite persistent treatment. (C) tings and result in major health problems in the United States. Summary Statement 168: ACE inhibitor–induced angio- (C) edema is treated with discontinuation of the drug therapy and ADRs result in major health problems in the United States. subsequent avoidance of all ACE inhibitors. (D) In a meta-analysis of inpatient ADR prospective studies, Summary Statement 169: Most patients who experience 15.1% of patients sustained ADRs, and 6.7% of patients angioedema during ACE inhibitor treatment are able to tol- experienced serious ADRs.195 Using the same data, the au- erate ARBs. (C) thors estimated that inpatient ADRs are responsible for Summary Statement 170: Patients with a history of angio- 106,000 annually in the United States. Depending on edema or C1 esterase inhibitor deficiency are at increased risk whether one uses the lower or upper limit of this confidence of more frequent and severe episodes of angioedema with the interval, inpatient ADRs constitute either the fourth or sixth administration of ACE inhibitors, so they should not receive leading cause of death in the United States.195 these drugs. (C) Although most drugs are prescribed for outpatients, few studies have evaluated the frequency and severity of ADRs in T. Biologic Modifiers this setting. In a 4-week, prospective cohort study of outpa- Summary Statement 171: Allergic drug reactions ranging tients followed up in primary care , 25% of patients from cutaneous lesions to severe anaphylaxis may occur reported ADRs, 13% of which were serious.196 In another during treatment with recombinant interferons. (C) retrospective study, 17% of outpatients reported ADRs due to Summary Statement 172: Both cutaneous and systemic a prescribed medication.197 allergic reactions have been reported after treatment with infliximab, a human monoclonal antibody against tumor ne- II. DEFINITIONS crosis factor ␣ (TNF-␣). (C) Summary Statement 2: ADRs are broadly categorized into Summary Statement 173: Both cutaneous and systemic predictable and unpredictable reactions. (D) allergic reactions have been reported after treatment with Summary Statement 3: Unpredictable reactions are subdi- both murine and humanized monoclonal antibodies. (C) vided into drug intolerance, drug idiosyncrasy, drug allergy, Summary Statement 174: Rare anaphylactic reactions to and pseudoallergic reactions. (D) Summary Statement 4: Drug intolerance is an undesirable anti-IgE humanized monoclonal antibody (omalizumab) were pharmacologic effect that occurs at low and sometimes sub- described during phase III clinical trials and during the post- therapeutic doses of the drug without underlying abnormali- marketing surveillance period. (C) ties of metabolism, excretion, or bioavailability of the drug. Summary Statement 175: The cytokine release syndrome (D) must be distinguished between anaphylactoid and anaphylac- Summary Statement 5: Drug idiosyncrasy is an abnormal tic reactions due to anticancer monoclonal antibodies. (C) and unexpected effect that is unrelated to the intended phar- U. Complementary Medicines macologic action of a drug. (D) Summary Statement 176: Allergic reactions may occur Summary Statement 6: Drug allergy reactions are immu- after use of complementary medicines such as bee pollen, nologically mediated responses that result in the production , and vitamins. (C) of drug-specific antibodies, T cells, or both. (B) Summary Statement 7: Manifestations of pseudoallergic V. Other Agents reactions mimic IgE-mediated allergic reactions, but they are Summary Statement 177: N-acetylcysteine may cause ana- due to direct release of mediators from mast cells and ba- phylactoid reactions. (C) sophils and do not require a preceding period of sensitization. Summary Statement 178: Anaphylactoid reactions and (B) deaths have been associated with intravenous iron prepara- ADRs are broadly categorized into predictable and unpre- tions, particularly iron-dextran. (C) dictable reactions.198 Predictable reactions are usually dose Summary Statement 179: Life-threatening anaphylactic re- dependent, are related to the known pharmacologic actions of actions have occurred after intravenous use of isosulfan blue the drug, and occur in otherwise healthy individuals. They are and Patent Blue V dyes. (C) estimated to comprise approximately 80% of all ADRs. Un- Summary Statement 180: Anaphylactoid reactions may predictable reactions are generally dose independent, are un- occur after treatment with colloid volume expanders, manni- related to the pharmacologic actions of the drug, and occur tol, Cremophor-EL, and preservatives. (C) only in susceptible individuals. Unpredictable reactions are Summary Statement 181: Preservatives and additives in subdivided into drug intolerance, drug idiosyncrasy, drug medications rarely cause immunologic drug reactions. (C) allergy, and pseudoallergic reactions.

VOLUME 105, OCTOBER, 2010 273.e24 Drug intolerance is an undesirable pharmacologic effect III: immune complex; type IV: cell mediated), whereas others that occurs at low and sometimes subtherapeutic doses of the cannot be classified because of lack of knowledge of their drug without underlying abnormalities of metabolism, excre- immunopathogenesis or a mixed mechanism. (C) tion, or bioavailability of the drug. Humoral or cellular im- Summary Statement 9: Allergic drug reactions may also be mune mechanisms are not thought to be involved, and a classified according to the predominant organ system in- scientific explanation for such exaggerated responses has not volved (eg, cutaneous, hepatic, renal) or according to the been established. A typical example is aspirin-induced tinni- temporal relationship to onset of symptoms (immediate, ac- tus occurring at usual therapeutic or subtherapeutic doses. celerated, delayed). (D) Drug idiosyncrasy is an abnormal and unexpected effect Summary Statement 10: To some extent, the structural that is unrelated to the intended pharmacologic action of a characteristics of drugs may permit predictions about the type drug. It is not mediated by a humoral or cellular immune of hypersensitivity reactions they are likely to cause. (C) response but is reproducible on readministration. Unlike drug Clinical presentations of drug allergy are often diverse, intolerance, it is usually due to underlying abnormalities of depending on type(s) of immune responses and target organ metabolism, excretion, or bioavailability. A typical example specificities). If immunopathogenesis is mixed, some drug is primaquine-induced hemolytic anemia in glucose-6-phos- reactions may be difficult to classify by criteria previously phate dehydrogenase–deficient individuals. established for naturally occurring human hypersensitivity. Drug allergy and hypersensitivity reactions are immuno- On the other , the characteristics and mechanisms of logically mediated responses to pharmacologic agents or many allergic drug reactions are consistent with the chief pharmaceutical excipients. They occur after a period of sen- categories of human hypersensitivity defined by the Gell- sitization and result in the production of drug-specific anti- Coombs classification of human hypersensitivity (immediate bodies, T cells, or both. hypersensitivity [type I], cytotoxic [type II], immune com- Pseudoallergic reactions, also called anaphylactoid (non– 199 IgE-mediated anaphylaxis) reactions, mimic anaphylactic al- plex [type IIII], and cell mediated [type IV]). lergic reactions. Unlike allergic reactions, pseudoallergic re- A. IgE-Mediated Reactions (Gell-Coombs Type I) actions do not require a preceding period of sensitization and Summary Statement 11: IgE-mediated reactions may occur are not due to the presence of specific IgE antibodies. after administration of a wide variety of drugs, biologicals, Pseudoallergic reactions are mediated by a diverse group of and drug formulation agents, with the most common agents agents, such as opiates, colloid volume expanders, basic being antibiotics. (C) polypeptide agents (eg, B, ACTH), radiocontrast Immediate hypersensitivity type I reactions are IgE medi- media, excipients (eg, Cremophor-EL), vancomycin, and oth- ated and result in immediate reactions, such as anaphylaxis. ers. Acute reactions to these substances are caused by direct These are exemplified by symptoms of urticaria, laryngeal release of mediators from mast cells and basophils, resulting edema, wheezing, and cardiorespiratory collapse, which typ- in the classic end organ effects that these mediators exert. ically occur within minutes of exposure to the drug. IgE- Direct mediator release occurs without evidence of a prior mediated hypersensitivity reactions may occur after admin- sensitization period, specific IgE antibodies, or antigen-anti- istration of a wide variety of drugs, biologicals, and drug body bridging on the –basophil cell membrane. The formulation agents. Common causes are large-molecular- reaction is immediate and often severe. Because it does not mass biologicals and many drugs (eg, penicillin). The most require a preceding period of sensitization, it may occur the first time that the host is exposed to these agents. The reac- important drug causes of immediate hypersensitivity reac- tions are of further interest because they can also be elicited tions are antibiotics. Other common drugs that cause such by small doses of the offending substance. It is possible that reactions are insulin, enzymes (asparaginase), heterologous some of these reactions could be based in part on nonimmu- antisera (equine antitoxins, antilymphocyte globulin), murine 100,200-205 nologic release of anaphylatoxins (C3a, C5a) through activa- monoclonal antibodies, protamine, and heparin. Al- tion of the alternative complement pathway. Neuropeptides lergic type I reactions have also been reported rarely after (eg, substance P) and endorphins may also activate and exposure to excipients, such as , carmine, vegetable induce mediator release from mast cells. Osmotic alterations gums, , sulfites, formaldehyde, polysorbates, and sul- may lead to nonspecific mediator release (eg, hyperosmolar fonechloramide.206-208 In this parameter, we will consider both mannitol), but such physical effects are more likely to occur ␤-lactam and non–␤-lactam antibiotics as the major proto- at local tissue sites, such as the nose or bronchi. types in this category. III. CLASSIFICATION OF IMMUNOLOGICALLY B. Cytotoxic Reactions (Gell-Coombs Type II) MEDIATED DRUG HYPERSENSITIVITY Summary Statement 12: Cytotoxic reactions are very seri- REACTIONS ous and potentially life-threatening. (C) Summary Statement 8: Some drug allergic reactions may Summary Statement 13: Immunohemolytic anemias have be classified by the Gell-Coombs classification paradigm of occurred after treatment with quinidine, ␣-methyldopa, and hypersensitivity (type I: IgE mediated; type II: cytotoxic; type penicillin. (C)

273.e25 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Summary Statement 14: Positive direct and indirect Summary Statement 18: The chief manifestations of fever, Coombs test results in immunohemolytic anemia may reflect rash, urticaria, lymphadenopathy, and arthralgias typically the presence of drug-specific IgG, complement, or an Rh appear 1 to 3 weeks after starting use of an offending agent. determinant autoantibody. (C) (C) Summary Statement 15: Immune-induced thrombocytope- Summary Statement 19: The prognosis for complete recov- nia may result from treatment with heparin, quinidine, pro- ery from serum sickness is excellent; however, symptoms pylthiouracil, gold salts, sulfonamides, vancomycin, and may last as long as several weeks. Treatment with systemic other drugs. (C) Platelet membrane damage is mediated corticosteroids and histamine1 receptor antihistamines may be mainly by drug–immune serum complexes, which are ad- required. (C) sorbed onto platelet membranes. (C) Summary Statement 20: Drug-induced immune complex Summary Statement 16: Immune-mediated granulocytope- disease may occur after exposure to heterologous proteins nia is uncommon but may be induced by cytotoxic antibodies (eg, thymoglobulin) or simple drugs (eg, penicillin, procain- synthesized in response to a variety of drugs. (C) amide, phenylpropanolamine). (C) Cytotoxic (type II) reactions are induced by complement- Type III reactions are mediated by immune complexes mediated cytotoxic IgM or IgG antibodies, which are formed formed in slight antigen excess. Serum sickness is the proto- in response to drug altered cell surface membranes. Classic type for type III reactions. Serum sickness was originally examples of this phenomenon are acquired hemolytic anemia noted when heterologous antisera were used extensively for induced by ␣-methyldopa and penicillin or thrombocytopenia passive immunization of infectious diseases. However, many caused by quinidine. Cytotoxic reactions are very serious and small-molecular-weight drugs are also associated with serum potentially life-threatening. sickness–like symptoms. These drugs include penicillin, sul- Immunohemolytic anemias due to drugs have clearly been fonamides, thiouracils, and phenytoin. Monoclonal antibody identified after treatment with quinidine, ␣-methyldopa, and have also been associated with serum sickness–like penicillin.209-211 In the case of penicillin, circulating antipeni- reactions to several agents, including infliximab, rituximab, cillin antibodies of the have been omalizumab, and . The chief manifestations of implicated.209 The condition is rare because it apparently fever, rash, urticaria, lymphadenopathy, and arthralgias typ- develops only in those individuals capable of synthesizing an ically appear 1 to 3 weeks after starting use of an offending atypical variety of IgG antipenicillin antibody. Penicillin drug and begin to subside when the drug and/or its metabo- binding by erythrocytes is an essential preliminary step in the lites are completely eliminated from the body.219 In previ- sensitization process and is more likely to occur in patients ously sensitized individuals, the reaction may begin within a receiving very large and prolonged dose regimens of penicil- few days after administration of the drug. Most of the clinical lin, as may be required in the long-term treatment of subacute symptoms are thought to be mediated by IgG and possibly bacterial . As previously discussed, positive di- IgM-drug complexes. However, the overall immune response rect and indirect Coombs test results in this condition also in immune complex reactions is heterogeneous because in may indicate the presence of complement on the red cell some cases, IgE antibodies can also be demonstrated and may membrane or an autoantibody to an Rh determinant. be associated with urticarial lesions seen early in the disease. Thrombocytopenia resulting from drug-induced immune A serum sickness–like reaction also can occur with reactive mechanisms has been well documented. The most thoroughly metabolites (Summary Statement 96). The prognosis for evaluated drugs in this category are quinine, quinidine, acet- complete recovery is excellent; however, symptoms may last aminophen, propylthiouracil, gold salts, vancomycin, and the as long as several weeks. Treatment consists of systemic 212-216 sulfonamides. Platelet membrane damage is mediated corticosteroids and histamine1 receptor antihistamines and in chiefly by circulating drug–immune serum complexes, which some cases nonsteroidal anti-inflammatory drugs (NSAIDs). are adsorbed onto platelet membranes. Polyclonal antibody therapy (Anti- globulin and Granulocytopenia also may be produced by cytotoxic an- thymoglobulin) is often used in solid tibodies synthesized in response to such drugs as pyrazolone for an immunologic induction and treatment of acute graft derivatives, phenothiazines, thiouracils, sulfonamides, and rejection.220 Immune complex–mediated illness (serum sick- anticonvulsives.217,218 Immunologically mediated destruction ness) manifested by fever, arthritis, rash, lymphadenopathy, of peripheral neutrophils occurs within minutes after read- and/or renal failure may occur at a prevalence rate between ministration of the drug and the immunologic specificity of 7% and 27% of renal transplant patients who receive poly- the antibody has been verified by passive transfer to nonsen- clonal antibody therapy.221,222. Other drugs that may induce sitive volunteers (in the pre-AIDS era). immune complex–mediated serum sickness or vasculitis in- clude penicillin, procainamide, hydralazine, and phenylpro- C. Immune Complex Reactions (Gell-Coombs Type III) panolamine.223-225 Summary Statement 17: Immune complex (serum sickness) reactions were originally described with use of heterologous D. Cell-Mediated Reactions (Gell-Coombs Type IV) antisera, but they may also be caused by some small-molec- Summary Statement 21: Contact dermatitis produced by ular-weight drugs and monoclonal antibodies. (C) topical drugs (such bacitracin, neomycin, glucocorticoste-

VOLUME 105, OCTOBER, 2010 273.e26 roids, local anesthetics, and antihistamines) and/or excipients In addition to reactions due to topical application, it is contained in topical formulations are due to cell-mediated postulated that Gell-Coombs type IV reactions are also re- reactions. (C) sponsible for some delayed cutaneous maculopapular erup- Summary Statement 22: It is postulated that Gell-Coombs tions due to oral antibiotics, such as amoxicillin and sulfon- type IV reactions are also responsible for some delayed amides.227,228 cutaneous maculopapular eruptions due to oral antibiotics, such as amoxicillin and sulfonamides. (C) E. Miscellaneous Syndromes Summary Statement 23: Patch testing at proper concentra- Summary Statement 25: Some drugs or classes of drugs are tions may be successful in detection of suspected contact associated with characteristic syndromes that often do not allergens. (B) conform to specific Gell-Coombs categories and sometimes Summary Statement 24: After avoidance is instituted, top- are referred to as mixed drug reactions (ie, a mixture of ical and/or systemic corticosteroids may be required for total immunologic mechanism). (C) clearing of the dermatitis (provided that these drugs were not Some drugs or classes of drugs are associated with char- the primary causes). (C) acteristic syndromes that often do not conform to specific Delayed hypersensitivity type IV reactions are mediated by Gell-Coombs categories. Table 2 highlights the spectrum of cellular immune mechanisms. A recently proposed modifica- drug allergic reactions and syndromes that will be discussed tion subdivides type IV reactions into 4 categories involving in greater detail in this parameter. Although various specific activation and recruitment of monocytes (IVa), eosinophils immune phenomena can often be demonstrated in these syn- (IVb), CD4ϩ or CD8ϩ T cells (IVc), and neutrophils (IVd).(1) dromes, their roles in the immunopathogenesis of the disease The classic reaction in this category is contact dermatitis, a have not been clearly established. Isolation of T-cell clones condition in which the topical induction and elicitation of with characteristic cytokine profiles in some of these reac- sensitization by a drug is entirely limited to the skin. It tions suggest that they may ultimately be classified into appears that Gell-Coombs type IV reactions are also respon- modified Gell-Coombs categories involving activation and sible for delayed cutaneous eruptions, such as maculopapular recruitment of monocytes and (IVa), eosino- exanthems due to antibiotics (eg, amoxicillin and sulfon- phils (IVb), cytotoxic T cells (IVc), and neutrophils (IVd). amides). Delayed hypersensitivity responses may also be 1. Hypersensitivity vasculitis systemic, involving lymphoid organs and other tissues Summary Statement 26: Many drugs, hematopoietic throughout the body. Sensitized T cells produce a wide array growth factors, cytokines, and interferons are associated with of proinflammatory cytokines that can ultimately lead to vasculitis of skin and visceral organs. (C) lymphocytic infiltrates, disseminated granulomata, and fibro- Many agents, hematopoietic growth factors, cytokines, and sis. It has been suggested there is a marked clinicopatholog- the interferons are suspected of causing widespread vascular ical similarity between some late-onset drug reactions and of skin and visceral organs.229,230 Frequently, graft va host reactions that are initiated and maintained by T the vascular changes occur during or at the endstage of 226 cells. drug-induced syndromes of serum sickness or drug fever. Allergic contact dermatitis after exposure to medications Drugs such as hydralazine, antithyroid medications, minocy- containing active drugs, additives, or lipid vehicles in oint- cline, and penicillamine are often associated with antinuclear ments is the most frequent form of drug-mediated delayed cytoplasmic antibody– or periantinuclear cytoplasmic anti- hypersensitivity. Morphologically, it usually cannot be dis- body–positive vasculitis-like disease.231 Antineutrophil cyto- tinguished from contact irritant dermatitis. Almost any drug plasmic antibody–positive vasculitis is also associated with applied locally is a potential sensitizer, but fewer than 40 hydralazine-induced systemic lupus erythematosus. Similar allergens produce most cases of contact dermatitis. Among findings also apply to propylthiouracil. A Henoch-Schönlein the drugs involved, the most universally accepted offenders syndrome with cutaneous vasculitis and glomerulonephritis are topical formulations of bacitracin, neomycin, glucocorti- may be induced by /levodopa.232 costeroids, local anesthetics, and antihistamines. Potent ex- cipient topical sensitizers include the , formalde- 2. Drug Rash With Eosinophilia and Systemic hyde, , lanolin, and thimerosal.206 Complex Symptoms (DRESS) Syndrome topical products may contain many potential and Summary Statement 27: The drug rash with eosinophilia additives, and in many instances the major component of a and systemic symptoms (DRESS) syndrome is a drug-in- complex mixture may not necessarily be the sensitizer. Pho- duced, multiorgan inflammatory response that may be life- toallergic dermatitis morphologically resembles allergic con- threatening. First described in conjunction with anticonvul- tact dermatitis and is caused by such drugs as sulfonamides, sant drug use, it has since been ascribed to a variety of drugs. thiazides, quinidine, , and fluoroquinolones. (C) Once induction sensitization has occurred, elicitation of der- Summary Statement 28: Anticonvulsant hypersensitivity matitis requires minimal exposure to light. Phototoxic, non- syndrome is mainly associated with aromatic anticonvulsant allergic reactions (eg, erythrosine) are histologically similar drugs and is related to an inherited deficiency of epoxide to photoallergic inflammatory responses. hydrolase, an enzyme required for the metabolism of arene

273.e27 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY oxide intermediates produced during hepatic metabolism. (B) the progression of symptoms that occur during a serum sick- Phenytoin, carbamazepine, and phenobarbital are considered ness–like reaction.232 Lymphadenopathy mimicking the clin- cross-reactive, but valproic acid, gabapentin, and lamotrigine ical manifestations of malignant (the pseudolym- are therapeutic alternatives. (C) It is slower in onset than phoma syndrome) was first reported in patients undergoing DRESS and presents with skin nodules, plaques, and lymph- anticonvulsant therapy. Two presentations are recognized: (1) adenopathy at times confused with lymphoreticular malignant DRESS 2 to 8 weeks after initiation of therapy and (2) a more tumors (ie, pseudolymphoma) (B) insidious onset with skin nodules and plaques, suggesting a The DRESS syndrome is a drug-induced, multiorgan in- pseudolymphoma without systemic symptoms.232 Hepatitis, flammatory response that may be life-threatening. First de- nephritis, and with atypical and scribed in conjunction with anticonvulsant drug use, it has eosinophils may be part of the syndrome. Facial edema since been ascribed to a variety of drugs. The terms describ- occurs in 25% of the patients. These multiorgan reactions ing this syndrome have varied in the literature, with various may be induced by phenytoin, carbamazepine, or phenobar- terms preferred by some authors, including phenytoin hyper- bital, and cross-reactivity may occur among all aromatic sensitivity syndrome, drug hypersensitivity syndrome, drug- anticonvulsants that produce toxic arene oxide metabolites induced hypersensitivity syndrome, and drug-induced de- Treatment involves removing the offending agent, and layed multiorgan hypersensitivity syndrome. Characteristic although corticosteroids have been used, their is features of DRESS vary and may include cutaneous eruptions unknown. Unlike Stevens-Johnson syndrome or toxic epider- (exanthems, erythema multiforme purpura), fever, eosino- mal necrolysis, there is almost never mucosal involvement philia (most but not all cases), hepatic dysfunction, renal with DRESS. Unlike serum sickness–like reactions, there is dysfunction, and lymphadenopathy.233 Case definitions for usually no . DRESS is atypical of most all other DRESS have recently been proposed for a multinational drug reactions in that symptoms and organ involvement can survey.234 These proposed inclusion criteria include 3 or more continue to progress after use of the offending agent has been of the following: hospitalization, reaction suspected to be discontinued. Furthermore, symptoms may persist for many drug related, acute rash, temperature higher than 38°C, en- months after drug therapy discontinuation. Relapses have larged lymph nodes at least 2 sites, involvement of at least 1 occurred after tapering of corticosteroids. There are limited internal organ, and hematologic abnormalities. Medications data on the use of intravenous immunoglobulin and other implicated in DRESS include anticonvulsants, sulfonamides, immunomodulatory agents in resistant cases.239 allopurinol, minocycline, dapsone, sulfasalazine, abacavir, , and hydroxychloroquine. DRESS is atypical from 3. Pulmonary Drug Hypersensitivity other drug allergic reactions in that the reaction develops Summary Statement 29: Pulmonary manifestations of al- later, usually 2 to 8 weeks after therapy is started; symptoms lergic drug reactions include anaphylaxis, lupuslike reactions, may worsen after the drug therapy is discontinued; and symp- alveolar or interstitial pneumonitis, noncardiogenic pulmo- toms may persist for weeks or even months after the drug nary edema, and granulomatous vasculitis (ie, Churg-Strauss therapy has been discontinued. Human herpesvirus 6 reacti- syndrome). Specific drugs are associated with different types vation has been detected in many patients with DRESS within of pulmonary reactions, such as bleomycin-induced fibrosis. 2 to 3 weeks of the eruption and may be an indicator of more (C) severe disease.235 Pulmonary manifestations of allergic drug reactions in- Systemic symptoms of the DRESS syndrome include fe- clude anaphylaxis, lupuslike reactions, alveolar or interstitial ver, involvement of internal organs, and an association with pneumonitis, edema, granulomatosis, and fibrosis.240 Acute previous exposure or infection with a herpesvirus (human pneumonitis with fever, rash, and eosinophilia occurs after herpesvirus 6).232,236 In addition to anticonvulsants, a variety treatment with nitrofurantoin, NSAIDs, and sulfasalazine. If of drugs have been reported to cause DRESS, including the drugs are not eliminated properly, these lesions may trimethoprim-sulfamethoxazole, minocycline, sulfasalazine, progress to a chronic course with interstitial fibrosis. Hyper- NSAIDs, D-penicillamine, hydrochlorothiazide, cyclosporine, sensitivity pneumonitis may occur in association with NSAID nevirapine, and allopurinol.237 In the case of allopurinol, toxic treatment. Biopsy-proven may occur intermediates may mediate the abnormal lymphocyte re- after use of sulfonamides, penicillin, and para-aminosalicylic sponses.238 The occurrence of this syndrome after use of acid. Patchy pneumonitis, pleuritis, and pleural effusion may valproic acid or gabapentin is rare. appear during various drug-induced lupus syndromes.241 Anticonvulsant hypersensitivity syndrome is life-threaten- Whether pleuropulmonary fibrosis has an immunologic basis ing and may occur after varying (usually longer than DRESS) is unknown at the present time. Characteristic histologic periods of exposure to anticonvulsive medications. It appears fibrotic changes are caused by certain cytotoxic drugs, such to result from an inherited deficiency of epoxide hydrolase, as bisulphan, , and bleomycin. Acute pul- an enzyme required for the metabolism of arene oxide inter- monary reactions produced by other fibrogenic drugs, such as mediates produced during hepatic metabolism of aromatic methotrexate, , and , are similar to anticonvulsant drugs. It is characterized by fever, a maculo- those of nitrofurantoin pneumonitis and therefore appear to papular rash, and generalized lymphadenopathy, resembling be mediated by hypersensitivity mechanisms.240 These le-

VOLUME 105, OCTOBER, 2010 273.e28 Table 4. Drug-Induced Lupus Erythematosus (DILE) Systemic DILE Cutaneous DILE

Incidence Rare More frequent cause of subcutaneous lupus erythematosus Drugs Implicated Hydralazine, procainamide, isoniazid, methyldopa, Hydrochlorothiazide, calcium channel blockers, ACE quinidine, minocycline, chlorpromazine inhibitors, systemic antifungal agents Onset of symptoms Gradual escalation of symptoms over months Onset of symptoms within 4-8 weeks Systemic Symptoms Arthralgias and myalgias frequent No systemic symptoms Cutaneous symptoms Photosensitivity, purpura, Photosensitive erythema, scaly annular plaques more frequent Serologic testing Antihistone antibodies Ͼ90% overall Antihistone antibodies Ͻ25% Anti-Ro/SSA and/or anti-La/SSB usually negative Anti-Ro/SSA and/or anti-La/SSB frequently positive

Abbreviation: ACE, angiotensin-converting enzyme. sions are sometimes confused with noncardiac pulmonary Cutaneous DILE differs from systemic DILE in respect to edema, which occurs after administration of , metha- several features. Drugs most commonly associated with cu- done, propoxyphene, or hydrochlorothiazide. The clinical taneous DILE include hydrochlorothiazide, calcium channel spectrum of pulmonary hypersensitivity reactions may in- blockers, angiotensin-converting enzyme (ACE) inhibitors, clude interstitial pneumonitis (with or without eosinophilia), and systemic antifungal agents.246 Anti-Ro and anti-SSA an- obliterans (with or without chronic organizing tibodies are usually present, whereas antihistone antibodies pneumonia), the pulmonary-renal syndrome associated with are much less frequent.244 The onset of cutaneous DILE is 240,242 D-penicillamine, and several granulomatous vasculitides. much faster than systemic DILE, with disease being triggered 4. Drug-Induced Lupus typically in 4 to 8 weeks. Summary Statement 30: Drug-induced lupus erythemato- 5. Drug-Induced Granulomatous Disease With or sus (DILE) can have systemic forms and predominantly cu- Without Vasculitis taneous forms. Procainamide and hydralazine are the most Summary Statement 32: The recognition of immunologi- frequently implicated drugs for systemic DILE, and antihis- cally mediated, drug-induced granulomatous disease with or tone antibodies are present in more than 90% of patients but without vasculitis has increased in recent years. (C) occur less commonly with minocycline, propylthiouracil, and Drug-induced, antineutrophil cytoplasmic antibody–posi- statins. (C) Summary Statement 31: Drugs most commonly associated tive patients may present either as the Churg-Strauss Syn- with cutaneous DILE include hydrochlorothiazide, calcium drome (CSS) or Wegener granulomatosis (WG), both of channel blockers, angiotensin-converting enzyme inhibitors, which are classified as systemic granulomatous vasculiti- 247,248 and systemic antifungal agents. Anti-Ro and anti-SSA anti- des. Case reports have documented their occurrence in bodies are usually present, where antihistone antibodies are patients receiving various drugs (, , acet- much less frequent. (C) aminophen, antibiotics, antithyroid drugs, and leu- DILE is thought to represent up to 10% of systemic lupus kotriene-modifying agents).249-253 Antithyroid drugs (eg, pro- erythematosus cases.243 Similar to idiopathic lupus, DILE can pylthiouracil) are more likely to induce WG and a lupuslike have systemic forms and predominantly cutaneous forms (Table syndrome, but a few instances of CSS have been reported.252 4). Systemic DILE usually occurs after years of exposure to the Several published investigations have attributed a higher offending drug and resolves within weeks to months after with- prevalence of CSS in association with antiasthma drugs, drawal of the causative agent. Procainamide and hydralazine are particularly the use of .254-256. This has been the most frequently implicated drugs, but causal evidence is also postulated to occur because of the oral steroid sparing effect convincing for isoniazid, methyldopa, quinidine, minocycline, of these agents with subsequent unmasking of quiescent CSS and chlorpromazine.244 The most frequent signs and symptoms as steroids are tapered, although CSS has occurred in some of systemic DILE are arthralgias, myalgias, fever, malaise, and -treated patients who did not receive prior weight loss. Hypocomplementemia and antibodies to double- glucocorticosteroids.251 However, given the inconclusive and stranded DNA (dsDNA) are rare, whereas antihistone antibodies contradictory reports on this subject, no direct causal effect of are present in more than 90% of patients with DILE overall but leukotriene modifiers has been established and further re- occur less frequently with minocycline, propylthiouracil, and search is needed.257 statins.244 DILE related to anti– ␣ (TNF-␣) drugs demonstrate several differences from classic DILE, in- 6. Immunologic Hepatitis cluding more frequent rash (Ͼ70%), antibodies to dsDNA Summary Statement 33: Immunologic hepatitis may occur (90%), and hypocomplementemia (Ͼ50%) and less frequent after sensitization to para-aminosalicylic acid, sulfonamides, antihistone antibodies.245 and phenothiazines. (C)

273.e29 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY There is strong circumstantial evidence that immunologic may assist with treatment of pruritus. Early treat- hepatitis occurs after sensitization to para-aminosalicylic ment of erythema multiforme minor with systemic cortico- acid, sulfonamides, and phenothiazines.258 Cholestatic jaun- steroids may prevent progression to the more serious dice is a prominent feature of induced by phe- erythema multiforme major/Stevens-Johnson syndrome. nothiazine, amoxicillin/clavuronic acid, and .259-261 b. Erythema Multiforme Major/Stevens-Johnson Syndrome Less well defined are possible immunologic aberrations as- Drugs are an important cause of the erythema multiforme sociated with hepatocellular changes occurring after halo- major/Stevens-Johnson syndrome (SJS) and toxic epidermal thane, anticonvulsives, erythromycin, indomethacin, and necrolysis (TEN). Thus far, more than a hundred drugs have isoniazid. been implicated as causes of these syndromes. In a large Drugs such as oxyphenisatin, methyldopa, nitrofurantoin, prospective cohort study, drugs associated with a high rela- , , pernoline, minocycline, and atorvastin tive risk of developing SJS or TEN were sulfonamides, may induce hepatocellular damage that mimics autoimmune cephalosporins, imidazole agents, and derivatives, hepatitis.262. Herbal agents, such as black cohosh and dai- whereas drugs in the moderate risk category included quin- saiko-to, may trigger . Whether these olones, carbamazepine, phenytoin, valproic acid, and glu- drugs or herbs unmask or induce autoimmune hepatitis or cocorticosteroids.264 Rarely, vancomycin may induce several cause drug-induced hepatitis with accompanying autoim- forms of bullous skin disease. One of these is subdermal, mune features is unknown. There are no generally available blistering disorder characterized by IgA deposition beneath diagnostic methods to distinguish between hepatic immuno- the basement membrane. Biopsy with direct immunofluores- allergic and toxic reactions due to drugs, such as . cence is required to distinguish this reaction from the SJS and 7. Blistering Disorders TEN, which can also be induced by this drug. As described Summary Statement 34: Erythema multiforme minor is a under the Physical Examination section (section V), target cell-mediated hypersensitivity reaction associated with vi- and bullous lesions primarily involving the extremities and ruses, other infectious agents, and drugs. It manifests as mucous membranes are characteristic of erythema multi- pleomorphic cutaneous eruptions, with target lesions being forme major, whereas the features of SJS are confluent pur- most characteristic. (C) puric macules on face and trunk and severe, explosive mu- Summary Statement 35: There is no consensus on the cosal erosions, usually at more than 1 mucosal surface, that distinction between erythema multiforme major and Stevens- are accompanied by a high temperature and severe constitu- Johnson syndrome. These disorders involve mucosal surfaces tional symptoms. Ocular involvement may be particularly and the skin. (D) serious. Liver, , and lungs may be involved singly or in Summary Statement 36: Use of systemic corticosteroids for combination. As soon as the diagnosis is established, use of treatment of erythema multiforme major or Stevens-Johnson the suspected drug should be stopped immediately. The use syndrome is controversial. (D) of glucocorticosteroid therapy is controversial.265-267 If it is Summary Statement 37: Toxic epidermal necrolysis (ie, started, it should probably be initiated early in the disease and Lyell syndrome) is distinguished from Stevens-Johnson syn- very high doses should be used.268 However, if this treatment drome by the extent of epidermal detachment. (D) is started too late in the disease (ie, 3 to 4 days after onset), Summary Statement 38: Systemic corticosteroids are asso- it is possible that TEN could supervene, in which case sys- ciated with increased mortality when used for the manage- temic glucocorticosteroids are contraindicated.265,269 ment of advanced toxic epidermal necrolysis (C). Treatment c. Toxic Epidermal Necrolysis with high-dose intravenous immunoglobulin is controversial. SJS and TEN are probably part of a single disease spec- (D) trum. According to a commonly used classification scheme, if Summary Statement 39: Toxic epidermal necrolysis should epidermal detachment is less than 10%, the disease is SJS, but be managed in a burn unit. (D) when epidermal detachment reaches 30% or more, the diag- a. Erythema Multiforme Minor nosis is TEN.270 In cases with detachment of 10% to 30% of Erythema multiforme minor appears to be a cell-mediated the , the 2 syndromes are considered overlapping. hypersensitivity reaction associated with , other infec- TEN is almost always drug induced and is manifested by tious agents, and drugs. It is manifested by pleomorphic widespread areas of confluent erythema followed by epider- cutaneous eruptions; at times bullous and target lesions are mal necrosis and detachment with severe mucosal involve- also characteristic. A specific form of erythema multiforme ment. Significant loss of skin equivalent to a third-degree minor may develop in the radiation field of oncologic patients burn occurs. Glucocorticosteroids are contraindicated in this receiving phenytoin for prophylaxis of caused by condition, which must be managed in a burn unit.265 There is brain metastases (EMPACT: EM associated with Phenytoin a significant risk of infection, and mortality rates as high as and Cranial ).263 If a drug cause is sus- 50% have been reported.271 TEN should be distinguished pected, use of the drug should be stopped immediately and from the scalded skin syndrome, a disorder caused by staph- the addition of glucocorticosteroids may be necessary. Anti- ylococcal bacterial and characterized by the massive

VOLUME 105, OCTOBER, 2010 273.e30 skin cleavage and separation in the uppermost epidermis. A munoglobulins are commonly observed.242 Renal vasculitis number of open-label, retrospective, and prospective noncon- has also been reported.293,294 trolled studies have demonstrated improved outcomes (such F. Other Classification Systems for Drug Allergy as lower mortality rates, shorter time to interruption of lesion Summary Statement 42: In addition to Gell-Coombs hy- progression, shorter time to complete reepithelialization) in persensitivity reactions, there are a number of other mecha- patients with TEN treated with high-dose intravenous immu- nistic and clinical classifications for drug allergy. (C) noglobulins (IVIGs).272-276 Other studies using similar meth- Summary Statement 43: The p-i concept (pharmacologic ods found no beneficial effects of IVIG on TEN.277-279 The interaction with immune receptors) is a recently proposed typical dose of IVIG used in these studies was approximately addition to drug hypersensitivity classification in which a 0.5 to 1 g/kg per day for 3 to 4 days. The drug binds noncovalently to a T-cell receptor, which may of IVIG is believed to be inhibition of Fas-Fas asso- lead to an immune response via interaction with a major ciated apoptosis, which has been found to be extensive in 280 histocompatibility complex receptor. (C) keratinocytes of patients with TEN. There are limited data Summary Statement 44: From a clinical standpoint, the to suggest that anti–TNF-␣ treatment is beneficial in 281,282 most practical method of classifying drug reactions is by TEN. predilection for various tissue and organ systems. (D) 8. Serum Sickness–Like Reactions Associated With Summary Statement 45: The structural characteristics of Specific Cephalosporins drugs and biological products may permit predictions about Summary Statement 40: Serum sickness–like reactions what type of hypersensitivity reactions to expect from certain caused by cephalosporins (especially cefaclor) usually are classes of therapeutic substances. (C) due to altered metabolism of the drug, resulting in reactive In addition to the Gell-Coombs human hypersensitivity intermediates. (B) classification, there are a number of drug reactions associated Cefaclor and to a lesser extent cefprozil are associated with with specific T-cell activation, for which immunopathogen- serum-sickness–like reactions characterized primarily by se- esis has not been fully established, such as drug fever and vere erythema multiforme and arthralgias. There is no evi- fixed drug reactions. The latter are caused by such drugs as dence of an antibody-mediated basis for this reaction.283-286 and sulfonamides. The term fixed is applied to Serum-sickness–like reactions to cefaclor appear to result this lesion because reexposure to the drug usually produces from altered metabolism of the parent drug, resulting in toxic recurrence of the lesion at the original site. reactive intermediate compounds.283 This altered metabolism The p-i concept (pharmacologic interaction with immune can often be documented in a parent of the patient.283 Anec- receptors) is a recently proposed addition to drug hypersen- dotally, affected patients later have tolerated other cephalo- sitivity classification. In this scheme, a drug binds nonco- sporins. In vitro tests for toxic metabolites have confirmed a valently to a T-cell receptor, which may lead to an immune lack of cross-reactivity between cefaclor and other cephalo- response via interaction with a major histocompatibility com- sporins.287 Therefore, patients with serum sickness–like reac- plex receptor. In this scenario, no sensitization is required tions to cefaclor and cefprozil may not need to avoid other because there is direct stimulation of memory and effector T 2,3 cephalosporins. cells, analogous to the concept of superantigens. From the clinical standpoint, the most practical method of 9. Immunologic Nephropathy classifying drug reactions is by predilection for various tissue Summary Statement 41: Immunologically mediated ne- and organ systems. Cutaneous drug reactivity represents the phropathies may present as interstitial nephritis (such as with most common form of restricted tissue responsiveness to methicillin) or as membranous glomerulonephritis (eg, gold, drugs. The pulmonary system is also recognized as a favorite penicillamine, and allopurinol). (C) site for certain drug hypersensitivity reactions. Other individ- The major example of drug-induced immunologic ne- ual tissue responses to drugs include cytotoxic effects on phropathy is an interstitial nephritis induced by large doses of blood components and hypersensitivity sequelae in liver, , methicillin, or sulfonamides.288,289 In addi- kidneys, and blood vessels. Some drugs, however, induce tion to symptoms of tubular dysfunction, these patients dem- heterogeneous immune responses and tissue manifestations. onstrate fever, rash, eosinophilia (especially in the urine), and Thus, sensitization to penicillin or its degradation products high levels of total IgE, which revert to normal on discon- may eventuate in anaphylaxis, morbilliform rashes, serum tinuation of use of the offending drug.290 The predominant sickness, drug fever, cytotoxic effects (eg, hemolytic ane- lesion of the induced by gold, penicilla- mia), hypersensitivity vasculitis, interstitial nephritis, or se- mine, and allopurinol is a membranous glomerulonephri- vere contact dermatitis if applied topically. Finally, the tem- tis.288,291 An immunologic basis of this lesion is suggested by poral relationship to onset of symptoms after administration deposition of IgG, IgM, and C3 in glomerular lesions.292 In of a specific drug may constitute another type of classifica- the rare pulmonary-renal syndrome induced by penicillamine, tion, ranging from immediate (minutes to an hour), acceler- “lumpy” intraglomerular deposits of complement and/or im- ated (1 hour to 3 days), or delayed (beyond 3 days).295

273.e31 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY To some extent, the structural characteristics of drugs and Parenteral and cutaneous administrations of a drug enhance biological products permit predictions about what type of the possibility of sensitization, whereas the oral route of hypersensitivity reactions to expect from certain classes of administration may be safer.301 Single doses of a prophylactic therapeutic substances. Allergic reactions to peptides and antibiotic are less likely to sensitize compared with high-dose proteins are most often mediated by either IgE antibodies or prolonged parenteral administration of the same drug. Fre- immune complex responses. Such reactions may also be quent repetitive courses of therapy are also more likely to mixed. In specific situations, the process may culminate in a sensitize, which accounts for the high prevalence of sensiti- multisystem, vasculitic disease of small and medium blood zation in patients with . vessels. Although immune responses induced by carbohy- Host factors and concurrent medical illnesses are signifi- drate agents are infrequent, anaphylaxis has been described cant risk factors. In the case of penicillin, allergic reactions after topical exposure to carboxymethycellulose.296 Any sin- appear to occur less frequently in children and in elderly gle or mixed variety of immune responses may occur after patients.302 Immaturity and senescence of the immune re- exposure to low-molecular-mass (Յ1,000Da) inorganic or sponse may account for these observations. Older age was organic medicinal chemicals. The immunogenic potential of found to be a risk factor for development of ADRs in hospi- such drugs is often determined by 1 or more reactive end talized patients,303 and this may be related to declining cog- products or metabolites, which haptenate with various body nitive function.304 In a prospective study, women were shown proteins. The parent compound itself is not immunogenic to have a 35% higher incidence of adverse cutaneous reac- because of its small size and inability to conjugate with tions to drugs than men.305 In another study, the odds ratio for proteins in a stable covalent linkage. Metabolism of drugs by women developing reactions to radiocontrast media was 20- cytochrome oxidase pathways may occur in the liver, skin, fold greater than for men.122 and phagocytic cells. In addition, patients with certain genetic A subset of patients shows a marked tendency to react polymorphisms of metabolic enzymes may be at higher to clinically unrelated drugs, especially antibiotics.27,306-308 risk for allergic and autoimmune disorders induced by These reactions encompass urticaria, rashes, serum sickness– drugs.283,297,298 As a general rule, increases in molecular mass like drug reactions, angioedema, anaphylaxis, and SJS. Com- and structural complexity are often associated with increased pared with monosensitive patients, many of these patients immunogenicity, at least as far as humoral-mediated hyper- show evidence of circulating histamine-releasing factors, as sensitivity is concerned. assessed by autologous serum skin tests.309 It has also been suggested that previous intolerance to NSAIDs might be a IV. RISK FACTORS risk factor for some patients with this condition.310 Allergic Summary Statement 46: The most important risk factors for reactions to multiple structurally unrelated antibiotics appear drug hypersensitivity may be related to the chemical property to occur more often in women.308 There are limited data to and molecular weight of drugs. (C) suggest a familial component to drug allergy, but the studies Summary Statement 47: Other drug-specific risk factors for are limited by a reliance on patient history (which is known drug hypersensitivity include the dose, route of administra- to be a poor predictor of drug allergy) and by lack of confir- tion, duration of treatment, repetitive exposure to the drug, matory testing or provocative challenges.311 and concurrent illnesses (eg, Epstein-Barr virus infection and A genetic relationship to histocompatibility antigenic de- amoxicillin rash). (C) terminants (HLA-DR3) exists in patients with rheumatoid Summary Statement 48: Host risk factors for drug hyper- arthritis who are treated with gold or penicillamine and sub- sensitivity include age, sex, atopy, underlying diseases (such sequently develop drug-induced nephropathy.312 Allergic re- as lupus, erythematous, and human immunodeficiency virus) actions to abacavir have been associated with the presence of and specific genetic polymorphisms. (C) HLA B 5701.97,98 Patients with systemic lupus erythematous The chemical properties, amount and duration of exposure appear to have an increased prevalence of drug reactions, to the drug, and host factors may all interact in the develop- although it is not clear that this predilection is causally related ment of drug allergy. Large-molecular-weight agents, such as to the underlying immunologic abnormalities or the fact that proteins and some polysaccharides, may be immunogenic and such patients are exposed more often to drugs.313,314 Patients therefore are much more likely to induce antibody-mediated with systemic appear to be at increased risk of drug hypersensitivity reactions, especially in atopic individ- pseudoallergic reactions to narcotics and vancomycin. The uals. On the other hand, specific structural moieties in non- presence of an atopic diathesis (, allergic protein medicinal chemicals are often critical determinants in asthma, and/or atopic dermatitis) predisposes patients to a inducing drug hypersensitivity. How these particular struc- higher rate of allergic reactions to proteins (eg, latex) but not tures (eg, ␤-lactam rings of penicillins and cephalosporins) to low-molecular-weight agents.315-317 Paradoxically, atopic are degraded is of crucial importance. Prolonged drug and patients appear to have a greater risk of non–IgE-mediated, metabolite(s) may occur because of genetic poly- pseudoallergic reactions induced by radiocontrast media.123 morphisms of metabolic enzyme pathways (eg, hydralazine, Asthma appears to be associated with a substantially in- ).299,300 creased risk of serious allergic reactions (including certain

VOLUME 105, OCTOBER, 2010 273.e32 causes of anaphylaxis) once an IgE antibody response to any thems, urticaria, angioedema, acne, bullous eruptions, fixed drug has developed.301,302 drug eruptions, erythema multiforme, lupus erythematosus, photosensitivity, psoriasis, purpura, vasculitis, pruritus, and V. CLINICAL EVALUATION AND DIAGNOSIS OF life-threatening cutaneous reactions, such as Stevens-Johnson DRUG ALLERGY syndrome, toxic epidermal necrolysis, exfoliative dermatitis, A. History and drug rash with eosinophilia and systemic symptoms Summary Statement 49: The history should focus on pre- (DRESS). (C) vious and current drug use and the temporal sequence of Because drug reactions may involve virtually any organ events between initiation of therapy and onset of symptoms. system, a careful physical examination is recommended. Cu- (C) taneous manifestations are the most common presentation for The first question facing the physician in the evaluation of drug allergic reactions. Characterization of cutaneous lesions a patient with a suspected ADR is whether the clinical prob- is important in regard to determining the cause, further diag- lem is drug related. The subsequent clinical evaluation and nostic tests, and management decisions. Numerous cutaneous diagnosis of unpredictable (type B) drug reactions is based on reaction patterns have been reported in drug allergy, includ- a number of clinical criteria: ing exanthems, urticaria, angioedema, acne, bullous erup- 1) The symptoms and physical findings are compatible with tions, fixed drug eruptions, erythema multiforme, lupus ery- an unpredictable (type B) drug reaction; thematosus, photosensitivity, psoriasis, purpura, vasculitis, 2) There is a temporal relationship between administration of pruritus, and life-threatening cutaneous reactions, such as the drug and an adverse event. Patients may develop drug Stevens-Johnson syndrome, toxic epidermal necrolysis, exfo- reactions after discontinuation of use of the drug. liative dermatitis, and drug rash with eosinophilia and sys- 3) The class and chemical structure of the drug have been temic symptoms.4 associated with unpredictable reactions; The most common cutaneous manifestation of drug aller- 4) In cases of drug allergic reactions, the patient has previ- gic reactions is a generalized (maculopapular erup- ously been exposed to the drug on 1 or more occasions tion). These lesions are pruritic, often beginning as macules (with the possible exception of serum sickness–like reac- that can evolve into and eventually may coalesce into tions). For , the prior exposure may have taken plaques. Drug-induced exanthems typically involve the trunk place either in utero or via . and spread outward to the limbs in a bilateral symmetric 5) There is no other clear cause for the presenting manifes- pattern. Many drug-induced exanthems are manifestations of tations in a patient who is receiving medications known to delayed-type hypersensitivity. The development of a drug cause hypersensitivity reactions; and exanthem typically evolves after several days of taking the 6) Skin test results and/or laboratory findings (if available) offending drug. With resolution of an exanthem, scaling may are compatible with drug allergic reactions. occur. This should be distinguished from the type of epider- For most drug reactions, these questions are answered on mal detachment seen in severe cutaneous reactions that oc- the basis of information derived from the history and physical curs early in the reaction. Drug-induced exanthems do not examination. A careful history of previous and current drug evolve into anaphylactic reactions because they are not IgE- use, focusing particularly on the temporal sequence of events mediated reactions. Many drugs are capable of causing ex- between initiation of therapy and onset of symptoms is prob- anthems; however, certain medications, such as allopurinol, ably the most useful information for the diagnosis of an , cephalosporins, antiepileptic agents, and allergic drug reaction. In this regard, specific knowledge antibacterial sulfonamides, are some of the more frequent about the and allergenicity of the involved culprit drugs.318 Symmetrical drug-related intertriginous and drugs often is valuable in trying to delineate the causal factor. flexural exanthema (SDRIFE) specifically refers to the dis- This is particularly important when a patient is receiving tinctive, sharply demarcated erythema of the gluteal/perianal multiple drugs. As previously discussed, general and specific area and/or V-shaped erythema of the inguinal/perigenital host risk factors should also be noted in the medical history. area along with involvement of at least 1 other intertriginous/ flexural region.319 This specific pattern of exanthem has been B. Physical Examination previously referred to as ; however, the Summary Statement 50: Physical examination should in- term SDRIFE has been proposed to distinguish this reaction clude all systems that could possibly account for the clinical from topical contact allergens. presentation. (C) Fixed drug eruptions recur at the same skin or mucosal site Summary Statement 51: Cutaneous manifestations are the on reintroduction of the causative drug. Typical fixed drug most common presentation for drug allergic reactions. Char- eruptions present as round or oval, sharply demarcated, red to acterization of cutaneous lesions is important in regard to livid, slightly elevated plaques, ranging from a few millime- determining the cause, further diagnostic tests, and manage- ters to several centimeters in diameter.320 They may also ment decisions. (C) present as vesicles, and mucosal lesions are usually bullous. Summary Statement 52: Numerous cutaneous reaction pat- Fixed drug eruptions have a predilection for the lips, , terns have been reported in drug allergy, including exan- and genitalia (especially in men). Fixed drug eruptions can

273.e33 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY occur with a number of medications, including , semide, penicillin, and sulfasalazine are some of the causative NSAIDs, and carbamazepine. drugs implicated in drug-induced . A Urticaria and angioedema are the most common manifes- similar with tense bullae is linear IgA bullous tations of IgE-mediated drug allergy. However, it is important disease, with vancomycin being the most commonly incrim- to recognize that non–IgE-mediated drug allergic reactions inated drug. Vancomycin-induced linear IgA bullous disease can manifest with urticaria and angioedema too. Urticaria is is not dose dependent, and the severity does not appear to the most common manifestation of serum sickness; however, correlate with serum vancomycin levels.325 the presence of maculopapular lesions of the sides of the Purpura and petechiae are often cutaneous stigmata of fingers and toes or a serpiginous distribution of such lesions vasculitis, which can be drug induced. Leukocytoclastic vas- along lateral aspects of both soles may be more specific for culitis may be drug induced by many drugs, including anti- serum sickness. Angioedema due to ACE inhibitors is likely biotics, NSAIDs, and . a bradykinin-mediated manifestation of angioedema. Erythema multiforme is a polymorphous maculopapular Photoallergic reactions may present with eczematous erup- lesion that spreads peripherally and clears centrally to form tions in a photodistribution on the face, “V” area of the , an annular pattern known as a “target” lesion. This consists of dorsa of hands, and arms, with sparing of the scalp, submen- 3 zones: an erythematous central that may , an tal, and periorbital areas. Phototoxic reactions typically edematous middle ring, and an erythematous outer ring. present with within minutes to hours of sunlight In an exaggerated form, erythema multiforme may exposure but may present with vesicles with severe reactions. progress to the development of and progressive in- Drug-induced cutaneous lupus may also present with erup- volvement of the mucous membranes. Although this symp- tions in a photodistribution, typically with erythema or scaly, tom complex is termed erythema multiforme major and is annular plaques. often used synonymously with the SJS, some clinicians spec- Lichenoid drug eruptions may resemble and ify that the 2 conditions have distinguishing features. Target present with violaceous, polygonal papules. Medications re- lesions, particularly on the extremities, are still present in ported to cause lichenoid drug eruptions include ACE in- erythema multiforme major, whereas widespread blistering hibitors, , NSAIDs, proton pump inhibitors, and purpuric macules of the face, trunk, and proximal extremities imatinib. are characteristic of SJS.265 At this stage, more than 1 muco- Palmar-plantar erythrodysesthesia (also known as hand- sal site is involved and there are progressive constitutional syndrome) presents typically 2 to 12 days after chemo- symptoms. The clinical presentation of SJS may evolve into therapy with edema and erythema of the palms and soles and TEN, a severe drug-induced skin disease in which apoptotic, may progress to blistering, ulceration, or necrosis.321 Doxo- epidermal cell death results in the separation of large areas of rubicin, especially the pegylated liposomal form, is a com- skin at the dermoepidermal junction, producing the appear- mon culprit. ance of scalded skin.265 SJS and TEN are probably part of a Several cutaneous drug reactions may present with pus- single disease spectrum, with epidermal detachment less than tules. Acne can occur with glucocorticoids, , lith- 10% in SJS, greater than 30% in TEN, and 10% to 30% ium, phenytoin, and isoniazid and is common with the im- detachment is considered an overlap syndrome. 322 munosuppressant sirolimus. Acute generalized eczematous Exfoliative dermatitis is a severe end-stage dermatosis that pustulosis (AGEP) is a rare type of drug eruption that begins usually progresses from other types of late-onset cutaneous with erythema or edema in the intertriginous areas or face. drug reactions and consists of large confluent areas of shed- Afterward, fine nonfollicular sterile pustules develop. Fever, ding scaly and erythematous epidermis. Systemic manifesta- neutrophilia, and, in one-third of cases, eosinophilia may also tions, such as chills and fever, are common. 323 be present. Atypical target lesions, blisters, and oral mu- Acute life-threatening drug reactions can involve the upper cosal involvement are uncommon but may be confused with and lower respiratory tracts and the cardiovascular system. SJS. Implicated drugs include antibiotics and calcium chan- For a more detailed discussion of signs and symptoms of nel blockers. AGEP is T-cell–mediated drug reaction with anaphylaxis, see the Anaphylaxis Practice Parameter.326 Drug drug-specific CXCL8 T cells secreting 8, result- 324 reactions may present as an isolated fever, occasionally with ing in a neutrophilic dermatitis. Finally, drug-induced a temperature in excess of 104°F. In addition, drug reactions Sweet syndrome may present with fever, painful nodules, may cause a wide array of physical abnormalities, including pustules, and plaques and a neutrophilic dermatosis. Granu- lesions, lymphadenopathy, hepatospleno- locyte colony-stimulating factor, sulfonamide antibiotics, and megaly, pleuropneumonopathic abnormalities, and joint ten- minocycline may all cause drug-induced Sweet syndrome. derness or swelling. With any drug reaction associated with Drug allergic reactions may also present with vesicles. the loss of skin integrity, secondary infection should be Drug-induced pemphigus is most often caused by drugs con- considered. taining a thiol group (eg, , penicillamine) and pre- sents with flaccid blisters. Drug-induced bullous pemphigoid C. General Clinical Tests presents with tense bullae on the extremities, trunk, and Summary Statement 53: Possible laboratory tests might occasionally mucous membranes. ACE inhibitors, furo- include but are not limited to a chest x-ray examination,

VOLUME 105, OCTOBER, 2010 273.e34 electrocardiography, a complete blood cell count with differ- large-molecular-weight biologicals is immediate hypersensi- ential, sedimentation rate or C-reactive protein, autoantibody tivity skin testing. (B) tests, and specific immunologic tests. (C) Summary Statement 55: Specialized immunologic tests are Routine laboratory evaluation appropriate to the clinical sometimes able to confirm the immunologic basis of drug- setting may be useful for the evaluation of a patient with induced cytotoxic reactions. (B) suspected drug reaction, depending on the history and phys- Summary Statement 56: Drug patch testing may be useful ical examination findings (see below). A complete blood cell for certain types of cutaneous drug reactions, including mac- count with a differential cell count and a total platelet count ulopapular exanthems, acute generalized exanthematous pus- may help to exclude the possibility of cytotoxic reactions. tulosis, and fixed drug eruptions, but generally is not helpful Eosinophilia may be observed as an accompaniment of drug for Stevens-Johnson syndrome or urticarial eruptions. The fever, immune complex syndromes, eosinophilic pneumo- lack of standardization of reagent concentrations may limit nias, and the Churg-Strauss Syndrome, although most drug the clinical usefulness of drug patch testing. (B) reactions are not associated with eosinophilia. If renal in- Summary Statement 57: Lymphocyte proliferation assays volvement is suspected (eg, serum sickness, vasculitis), uri- may have utility as retrospective indicators of cell-mediated nalysis should be considered, looking for the presence of drug reactions, but their positive and negative predictive , casts, and eosinophils. The presence of urine values have not been determined and they are not available in eosinophils combined with an increase in total IgE may most medical centers. (C) Two criteria are used to demonstrate the immunologic suggest the presence of interstitial nephritis.290 basis of an adverse drug reaction: (1) detection of an immune The following tests may be helpful for identifying inflam- response to the drug or its metabolite(s) and (2) demonstra- mation associated with drug-induced vasculitis. These in- tion that the immune response is causally related to the clude measurement of a sedimentation rate (or C-reactive immunopathological sequelae in an affected individual. Al- protein), complement tests (looking for evidence of consump- though an immune response to a drug is an essential compo- tion indicated by reduced total complement or complement nent of all immunologic drug reactions, it does not prove that components) and several autoantibody tests (antinuclear an- the patient’s symptoms are due to a drug allergy. The second tibody [ANA], antinuclear cytoplasmic antibody [c-ANCA], criterion concerning the drug’s immunopathological role in and perinuclear cytoplasmic antibody [p-ANCA]). A positive the reaction is more difficult to document. In the case of ANA result may point to the diagnosis of the drug-induced immediate hypersensitivity reactions mediated by IgE anti- lupus syndrome induced by drugs such as procainamide and bodies, demonstration of the presence of drug specific IgE is hydralazine. Abnormalities in c-ANCA or p-ANCA fre- usually taken as sufficient evidence that the individual is at quently occur in drug-induced systemic vasculitides and the significant risk of having a type I reaction if the drug is Churg-Strauss syndrome.229 In serum sickness–like reactions, administered. This is helpful in the case of high-molecular- several nonspecific techniques may at times be helpful in weight agents.328 Penicillin is the only low-molecular-weight certain situations. The most common test for de- agent for which validated testing has been documented (see tection of immune complexes is a test for cryoglobulins or section VII on penicillin testing for details).17,328 Insufficient cold precipitable serum protein. C1q binding and Raji cell knowledge about drug degradation products and/or metabo- assays are also available for detection of immune complexes, lites and how they are conjugated with body proteins has been but these are rarely necessary in the routine evaluation of an impediment to developing either skin or in vitro assays for drug-induced serum sickness–like reactions. Positive test re- assessing immune responses to most small-molecular-weight sults are helpful, but negative test results do not exclude the drug chemicals. possibility of immune complex disease. The presence of other isotypic antibody classes (eg, drug- A retrospective diagnosis of anaphylaxis may be made by specific IgG4) or cell-mediated often is poorly detecting an increase in serum total tryptase levels above correlated with immunopathological mechanisms because baseline or in serum mature tryptase (also known as many individuals receiving drugs may demonstrate drug- ␤-tryptase), which peak 0.5 to 2 hours after drug administra- specific immune responses but do not react adversely to the tion and then decrease with a half-life of approximately 2 drug, even if challenged. Thus, the utility of specific immu- hours. Practically, an elevated level may be detected in the nologic tests (apart from IgE-mediated syndromes) is limited serum for 2 to 4 hours (or more) after the reaction, depending in most instances of drug hypersensitivity. At best, such tests on the magnitude of hypotension, which correlates with the provide adjunctive support for the clinical diagnosis. peak elevation of serum mature or total tryptase. An elevated Assessment of drug specific IgE antibodies induced by 24-hour urine histamine and/or N-methylhistamine also may many high-molecular-weight and several low-molecular- be detected as a clinical indicator of anaphylaxis.327 weight agents may be useful for confirming the diagnosis and prediction of future IgE-mediated reactions, such as anaphy- D. Specific Tests laxis and urticaria.17,317,328 Immediate type skin tests are usu- Summary Statement 54: The most useful test for detecting ally the most sensitive diagnostic tests, but in certain cases IgE-mediated drug reactions caused by penicillin and many where skin testing is not possible (ie, a negative histamine

273.e35 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY control test result, dermatographism or generalized eczema), agreement among investigators about the value of this assay specific IgE in vitro assays (eg, RAST, Immunocap, Immu- in evaluating drug allergies because neither its positive nor nolite) are available, although most are not adequately stan- negative predictive value has been systematically investi- dardized. In the case of small-molecular-weight drugs, vali- gated. The lymphocyte transformation test has recently be- dated and reliable skin test reagents are only available for come commercially available for selected drugs, but there are penicillin. Relatively few studies with small numbers of pa- no published studies using these assays, either alone or in tients have evaluated the specificity and sensitivity of third- comparison with previous independent assays. One potential generation assays for detection of penicillin specific IgE in advantage of the lymphocyte transformation test for some vitro.5,6 These studies demonstrate relatively high specificity patients is that it is possible to obtain in vitro evidence of (97%-100%) but lower sensitivity (29%-68%) for penicillin lymphocyte transformation by the parent drug itself and liver specific IgE. Therefore, although a positive in vitro test result microsomal products of the drug, thereby bypassing the need for penicillin specific IgE is highly predictive of penicillin for precise knowledge of metabolic determinants.334,335 Al- allergy, a negative in vitro test result does not adequately though the general clinical applicability of these tests has not exclude penicillin allergy. Immunoassays for penicillin spe- been validated in any large-scale study, a number of investi- cific IgE antibodies are less sensitive than skin tests and gators have shown that drugs may induce both CD4ϩ and ϩ therefore skin testing is preferred. More detailed information CD8 T-cell responses and drug specific TH1 and/or TH2 about the methods, reliability, and predictive capability of responses.227,228,336-338 The basophil activation test is a recently skin test reagents for the diagnosis of immediate drug allergic described method of evaluating expression of CD63 on ba- reactions may be found in sections V and VII. It should be sophils after stimulation with an allergen.7 There are limited emphasized that neither immediate skin nor in vitro tests for data using this method to evaluate patients with possible IgE antibodies are diagnostic of cytotoxic, immune complex, allergies to ␤-lactam antibiotics and NSAIDs.8-10 Further confir- or cell-mediated drug-induced allergic reactions. matory studies, especially with commercially available tests, are Both direct and indirect Coombs tests are often present in needed before its general acceptance as a diagnostic tool. drug-induced hemolytic anemia. This may reflect the pres- ence of complement and/or a drug on the red cell membrane E. Tissue Diagnosis or an Rh determinant autoantibody (eg, as occurs with Summary Statement 58: In complex cases where multiple ␣-methyldopa). Sensitive drug-specific assays for IgG and drugs are involved without a clear-cut temporal relationship, IgM antibodies have been developed. Although these may be a skin biopsy may be useful in suggesting a drug-induced useful as diagnostic adjuncts, elevated levels can occur in eruption. However, there are no absolute histologic criteria individuals who receive the drug and do not experience a for the diagnosis of drug-induced eruptions, and a skin biopsy clinical reaction.329 Complement-dependent assays to detect may not definitively exclude alternative causes. (C) drug-specific cytotoxic antibodies have also been reported. Occasionally biopsies of involved organs may define spe- However, by and large, these tests are only available in cific histopathological lesions. Skin biopsies may also be of specific research laboratories and therefore are not clinically value in the diagnosis and management of drug allergic applicable for most drugs. reactions. However, they usually are not helpful for implicat- The diagnosis of contact dermatitis can be verified by ing a particular drug. In complex cases where multiple drugs patch testing. The details of this technique are discussed in are involved without a clear-cut temporal relationship, a skin greater detail in the diagnostic testing practice parameter.330 biopsy may be useful in suggesting a drug-induced eruption. In recent years there have been reports concerning the diag- Skin biopsies are useful in differentiating vasculitis, bullous nostic utility of patch tests with systemically administered diseases, and contact dermatitis.265 However, there are no drugs in non–IgE-mediated cutaneous drug reactions.331,332 absolute histologic criteria for the diagnosis of drug-induced Drug patch testing may be useful for certain types of cuta- eruptions, and a skin biopsy may not definitively exclude neous reactions, including maculopapular exanthems, acute alternative causes.16 Furthermore, features suggestive of drug generalized exanthematous pustulosis, and fixed drug erup- exanthems, such as interface dermatitis with vacuolar alteration tions,12-14 but generally is not helpful for SJS or urticarial of keratinocytes, foci of spongiosis, and tissue eosinophilia, are eruptions.12,15 A positive reaction may be useful by identify- not specific and may be seen with other cutaneous diseases. ing a specific drug in a patient receiving multiple drugs, A liver biopsy helps to differentiate between cholestatic provided that it is properly compared with a group of negative and hepatocellular drug reactions but does not identify the controls. The lack of standardization of reagent concentra- specific cause. Membranous glomerulonephritis initiated by tions may limit the clinical usefulness of this procedure; deposition of immune complexes in the kidney can be readily however, recommendations for a standardized approach to identified by immunofluorescent stains for IgG, IgM, and drug patch tests have been proposed.333 complement in renal biopsy specimens.292 In interstitial ne- The lymphocyte transformation test has been studied as an phritis, fluorescent antibody studies of renal biopsy speci- in vitro correlate of drug-induced cellular reactions.334 This is mens reveal that implicated drugs bind to tubular basement used primarily as a retrospective test and is not clinically membranes and may induce an immune response to bound available in most medical centers. There is considerable dis- antigen or the modified basement membrane protein. Lung

VOLUME 105, OCTOBER, 2010 273.e36 biopsies also may be helpful for identifying conditions such type B, unpredictable drug reaction. For some reactions, as interstitial fibrosis and eosinophilia. simple withdrawal of the drug may be all that is required for treatment. Acute anaphylactic reactions should be treated as VI. MANAGEMENT AND PREVENTION OF DRUG described elsewhere.326 Immune complex reactions usually HYPERSENSITIVITY REACTIONS resolve spontaneously once the antigen is cleared. However, A. General Summary Statement 59: Ideally ADRs should be pre- therapy with antihistamines and possibly glucocorticosteroids vented. Steps to prevent allergic drug reactions include (1) a and/or NSAIDs may be useful for control of urticaria, joint careful history to determine host risk factors, (2) avoidance of symptoms, or vasculitis. Glucocorticosteroids may also be cross-reactive drugs, (3) use of predictive tests when avail- required for the treatment of drug-induced hemolytic, throm- able, (4) proper and prudent prescribing of drugs (especially bocytopenic, or granulocytic cytopenias, especially in situa- antibiotics) that are frequently associated with adverse reac- tions where the responsible drug must be continued as a tions, (5) use of oral drugs when possible, and (6) documen- life-saving measure. tation of ADR in the patient’s medical record. (D) Allergic drug reactions or a history of such reactions are Summary Statement 60: For some allergic drug reactions, occasionally encountered in other clinical situations where withdrawal of the drug may be all that is required for treat- continued use of the drug is imperative. Among the most ment. (C) important conditions for which continued drug use may be Summary Statement 61: Anaphylactic drug reactions re- justified are diabetic ketoacidosis, bacterial endocarditis, in- quire prompt emergency treatment as discussed extensively flammatory bowel disease, , AIDS, and pulmo- in “The Diagnosis and Management of Anaphylaxis: An nary tuberculosis. Primary and secondary prevention of cor- Updated Practice Parameter.” (B) onary artery disease and may also justify the use of Summary Statement 62: Glucocorticosteroids may be re- medications to which patients have experienced hypersensi- quired for immune complex reactions, drug-induced hemato- tivity reactions. When no equally effective alternative drug is logic diseases, early stages of erythema multiforme major/ available for therapy, the risk of continued administration of Stevens-Johnson syndrome, and contact sensitivities. (C) the offending drug may be less than the risk of not using the Drugs should be prescribed only for valid indications and drug. combinations of drugs should be used sparingly. This is B. Induction of Drug Tolerance especially important in individuals who have had multiple Summary Statement 63: What has often been referred to as reactions to various drugs. Ideally, ADRs should be pre- drug desensitization is more appropriately described in this vented. Steps to prevent allergic drug reactions include (1) a parameter as a temporary induction of drug tolerance. (D) careful history to determine host risk factors, (2) avoidance of cross-reactive drugs, (3) use of predictive tests when avail- Summary Statement 64: Induction of drug tolerance mod- able, (4) proper and prudent prescribing of drugs (especially ifies a patient’s response to a drug to temporarily allow antibiotics) that are frequently associated with adverse reac- treatment with it safely. It is only indicated in situations tions, (5) use of oral drugs when possible, and (6) documen- where an alternate non–cross-reacting medication cannot be tation of ADR in the patient’s medical record. used. (B) Patients should be questioned directly concerning previous Summary Statement 65: Through various mechanisms, in- drug reactions, and medical records should be reviewed for duction of drug tolerance procedures induce a temporary state previous notations of drug allergy. Cross-reactivity between of tolerance to the drug that is maintained only as long as the chemically related drugs should be considered. Orally admin- patient continues to take the specific drug. (B) istered drugs are less likely to produce reactions than drugs What has often been referred to as drug desensitization is given by the topical or parenteral route. MedicAlert tags and more appropriately described in this parameter as a temporary bracelets represent a useful way of alerting pro- induction of drug tolerance. Drug tolerance is defined as a viders to a previous severe allergic reaction, although histor- state in which a patient with a drug allergy will tolerate a drug ical diagnoses of drug allergy may not be an indicator of without an adverse reaction. Drug tolerance does not indicate current risk. Even so, the drug should not be given until the either a permanent state of tolerance or that the mechanism patient’s current status is evaluated. involved was immunologic tolerance. Induction of drug tol- A few states now require that the names and concentrations erance procedures modify a patient’s response to a drug to of all medications appear on prescription labels. This is a temporarily allow treatment with it safely. They are indicated useful advance that helps to ensure that the patient is being only in situations where an alternate non–cross-reacting educated about prescribed medications. In addition, the rou- medication cannot be used. Induction of drug tolerance can tine establishment of individual patient drug profiles by some involve IgE immune mechanisms, non-IgE immune mecha- and commercial facilitates identification nisms, pharmacologic mechanisms, and undefined mecha- of potential allergic reactions. nisms (Table 1). All procedures to induce drug tolerance The management of drug allergy begins with the suspicion involve administration of incremental doses of the drug. that any unexplained clinical manifestation may represent a Through various mechanisms, these procedures induce a tem-

273.e37 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY porary state of tolerance to the drug that is maintained only as hours, and the typical starting dose is in the microgram range. long as the patient continues to take the specific drug. (B) When there is a definite medical indication for the agent in Immunologic IgE induction of drug tolerance (also known question, either induction of tolerance or graded challenge as drug desensitization) is the progressive administration of procedures may be considered, depending on the history of an allergenic substance to render effector cells less reactive. the previous reaction and the likelihood that the patient is These procedures typically are done within hours, and the currently allergic to that agent. The goal of induction of typical starting dose is in the microgram range. The proce- tolerance is to modify an individual’s immune response to a dure can be performed via oral, intravenous, or subcutaneous given drug to allow treatment with it safely. If there is a low routes. There are no comparative studies to compare the likelihood of drug allergy, a graded challenge or test dose to safety of different routes of induction of drug tolerance, such the specific drug in question may provide a useful confirma- as oral vs intravenous. The resulting state is temporary, and tion that administration of the drug will not result in an its maintenance requires continued administration of the of- immediate reaction. The purpose of a graded challenge is to fending drug. Induction of drug tolerance procedures vary cautiously administer a drug to a patient who is unlikely to be with individual drugs, and they are intended for agents that allergic to it when there is no intention to alter the immune induce IgE-mediated reactions and, in some cases, for ana- response. This differs from procedures that induce drug tol- phylactoid (non–IgE-mediated anaphylaxis) reactions (such erance because graded challenges do not alter the patient’s as for paclitaxel and other chemotherapeutic agents). For underlying sensitivity to the agent. Patients who tolerate a example, in penicillin induction of drug tolerance, the initial graded challenge are considered to not be allergic to the drug dose is typically approximately 1/10,000 of the full therapeu- and are not at increased risk for future reactions compared tic dose.339-341 Further dosage increases are typically twice the with the general population. The use of prophylactic medi- previous dose and are administered at 15- to 30-minute in- cations to prevent systemic reactions in these procedures is tervals until therapeutic levels are achieved. The duration of optional. These protocols require the supervision of a health the procedure varies, depending on the drug and route of care professional with previous experience performing these administration, but, in most cases, can be accomplished procedures. within 4 to 12 hours. Induction of drug tolerance should be The choice of whether to introduce a clinically indicated performed in an appropriate setting, supervised by drug via graded challenge or via induction of drug tolerance familiar with the procedure, with continual monitoring of the mainly depends on the likelihood that the patient is allergic at patient and readiness to treat reactions, including anaphy- the time of the procedure. Patients who, based on their history laxis, should it occur. Induction of drug tolerance protocols and/or diagnostic test results, are unlikely to be allergic to a are available for a variety of drugs, including virtually all drug may undergo graded challenge. For example, if penicil- classes of antibiotics, insulin, chemotherapeutic agents, and lin skin testing is unavailable and a patient with a history of biological agents, such as humanized monoclonal antibod- a mild pruritic rash during penicillin treatment 30 years ago ies.56,342-352 In most cases, desensitization results in reversal of requires penicillin therapy, it would be reasonable to admin- skin test reactivity from positive to negative.340,353-355 Approx- ister penicillin via graded challenge. Patients who have a imately a third of patients who undergo penicillin induction relatively higher likelihood of being allergic to a drug should of drug tolerance experience allergic reactions, which are undergo an induction of drug tolerance procedure. For exam- generally mild and occur predominantly after the procedure, ple, if penicillin skin testing is unavailable and a patient with during treatment with penicillin.339,340,353 In the case of induc- a recent history of penicillin-induced anaphylaxis requires tion of drug tolerance with chemotherapeutics, 11% of pa- penicillin, it should be administered via induction of drug tients experienced allergic reactions, none of which prevented tolerance. When the likelihood of allergy is unknown, pa- completion of the procedure.356 Example protocols for vari- tients should undergo induction of drug tolerance. ous Immunologic IgE induction of drug tolerance procedures Graded challenge (or induction of drug tolerance) should are given in Tables 5, 6, 7, and 8. almost never be performed if the reaction history is consistent D. Immunologic Non-IgE Induction of Drug Tolerance with a severe non–IgE-mediated reaction, such as SJS, TEN, for Nonanaphylactic Reactions interstitial nephritis, hepatitis, or hemolytic anemia. Further- Summary Statement 67: For some delayed non–IgE-medi- more, these procedures are not indicated for all drug reac- ated cutaneous reactions, immunologic non-IgE induction of tions, such as ACE inhibitor angioedema. drug tolerance may be performed to allow treatment with the C. Immunologic IgE Induction of Drug Tolerance (Drug drug. However, it is generally contraindicated, with rare Desensitization) exceptions, for serious non–IgE-mediated reactions, such as Summary Statement 66: Immunologic IgE induction of Stevens-Johnson syndrome or toxic epidermal necrolysis. drug tolerance (drug desensitization) is the progressive ad- One example of when the benefit of treatment may outweigh ministration of an allergenic substance to render effector cells the risk of reaction is imatinib for treatment of malignant less reactive. These procedures typically are done within tumors. (C)

VOLUME 105, OCTOBER, 2010 273.e38 Table 5. Penicillin Oral Immunologic IgE Induction of Drug Table 7. Example of Intravenous Cephalosporin IgE Induction of Tolerance (eg, Desensitization) Protocol.679 Drug Tolerance Protocola Penicillin, Amount, Dose given, Cumulative Preparation of Solutions Stepa mg/mL mL mg dose, mg Volume of diluent Total to be Final 1 0.5 0.1 0.05 0.05 (eg, 0.9% sodium injected in concentration, 2 0.5 0.2 0.1 0.15 chloride) each bottle mg/mL 3 0.5 0.4 0.2 0.35 Solution 1 250 ml 10 mg 0.04 4 0.5 0.8 0.4 0.75 Solution 2 250 ml 100 mg 0.4 5 0.5 1.6 0.8 1.55 Solution 3 250 ml 1000 mg 4 6 0.5 3.2 1.6 3.15 7 0.5 6.4 3.2 6.35 Induction of Drug Tolerance Protocol 8 5 1.2 6 12.35 Rate, Time, Administered Cumulative Step Solution 9 5 2.4 12 24.35 mL/h min dose, mg dose, mg 10 5 5 25 49.35 11 50 1 50 100 1 1 2 15 0.02 0.02 12 50 2 100 200 2 1 5 15 0.05 0.07 13 50 4 200 400 3 1 10 15 0.1 0.17 14 50 8 400 800 4 1 20 15 0.2 0.37 Observe patient for 30 minutes, then give full therapeutic dose 5 2 5 15 0.5 0.87 by the desired route. 6 2 10 15 1 1.87 a Interval between doses is 15 minutes. 7 2 20 15 2 3.87 8 2 40 15 4 7.87 9 3 10 15 10 17.87 Immunologic non-IgE induction of drug tolerance proce- 10 3 20 15 20 37.87 11 3 40 15 40 77.87 dures are intended for patients who require a given drug to 12 3 75 184.4 922.13 1000 which they have previously experienced delayed non–IgE- mediated, typically cutaneous reactions. These are typically a Full dose equals 1,000 mg. Total time was 349.4 minutes. performed over hours to days with an initial dose in the milligram range.74,357,358 Examples of reactions in which these ening illness outweighs the risk of a potentially life-threaten- procedures may be used are trimethoprim-sulfamethoxazole– ing reaction. Table 9 depicts a rapid (6-hour) procedure, induced typical delayed drug eruptions in human immunode- whereas Table 10 depicts a slower 10-day outpatient proce- ficiency virus–positive patients, as well as some delayed dure for immunologic non-IgE induction of drug tolerance to cutaneous reactions due to sulfasalazine. The mechanism of trimethoprim-sulfamethoxazole. this drug tolerance induction procedure is unknown. For certain conditions (eg, SJS, TEN, exfoliative dermatitis), readministration is generally contraindicated, with rare ex- Table 8. Vancomycin Induction of Drug Tolerance Procedure344a ceptions, such as when benefit of treatment of a life-threat- Concentration Infusion Vancomycin Time, Cumulative of vancomycin, rate, infusion rate, min dose, mg mg/mL mL/min mg/min Table 6. Representative Paclitaxel Immunologic IgE Induction of Drug Tolerance (eg, Desensitization) Protocol.56 0 0.0001b 1.0 0.00010 0 10 0.001 0.33 0.00033 0.0010 a Rate, Time, Dose given, Cumulative Step Solution c mL/h min mg dose, mg 20 0.001 1.0 0.001 0.0043 30 0.01 0.33 0.0033 0.0143 1 A 2 15 0.006 0.006 40 0.01 1.0 0.01 0.047 2 A 5 15 0.015 0.021 50 0.1 0.33 0.033 0.147 3 A 10 15 0.03 0.051 60 0.1 1.0 0.1 0.48 4 A 20 15 0.06 0.111 70 1 0.33 0.33 1.48 5 B 5 15 0.15 0.261 80 1 1 1 4.78 6 B 10 15 0.3 0.561 90 10 0.22 2.2 14.8 7 B 20 15 0.6 1.161 100 10 0.44 4.4 37 8 B 40 15 1.2 2.361 a Rest of infusion maintained at 4.4 mg/min of vancomycin until final 9 C 10 15 3 5.361 dosage reached. Antihistamine pretreatment and concurrent treat- 10 C 20 15 6 11.361 ment used during protocol. 11 C 40 15 12 23.361 b Typical starting concentration in patients with severe vancomycin 12 C 75 221.3 276.639 300 reactions. a Solution A is 0.012 mg/mL (3 mg in 250 mL); solution B, 0.12 mg/mL c Typical starting concentration in patients with moderate vancomycin (30 mg in 250 mL); and solution C, 1.2 mg/mL (300 mg in 250 mL). reactions.

273.e39 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Table 9. Six-Hour Trimethoprim-Sulfamethoxazole Induction of aspirin is required for patients to remain in a tolerant state.359 Drug tolerance Procedure82a Leukotriene-modifying agents have been found to diminish Volume of the lower respiratory asthmatic response during aspirin de- Drug Concentration Time, Step TMP-SMX dosage of TMP-SMX min sensitization and therefore should be considered as pretreat- solution, mL ment for patients with AERD not already taking one of these 362,363 1 0.2/1 ␮g 8/40 ␮g/mL 0.025 0 agents. Once patients are desensitized, universal cross- 2 0.6/3 ␮g 8/40 ␮g/mL 0.075 30 reactivity with all NSAIDs is achieved. One indication for 3 1.8/9 ␮g 8/40 ␮g/mL 0.225 60 aspirin desensitization is patients with AERD who require 4 6/30 ␮g 8/40 ␮g/mL 0.75 90 aspirin (eg, cardiovascular disease).364 The other indication is 5 18/90 ␮g 8/40 ␮g/mL 2.25 120 poorly controlled AERD despite use of appropriate medica- 6 60/300 ␮g 8/40 ␮g/mL 7.5 150 tions or patients who require long-term treatment with sys- 7 0.2/1 mg 80/400 ␮g/mL 2.5 180 temic corticosteroids to control their respiratory disease. 8 0.6/3 mg 80/400 ␮g/mL 7.5 210 Several long-term studies of patients maintained with long- 9 1.8/9 mg 0.8/4 mg/mL 2.25 240 term aspirin desensitization demonstrated improved clinical 10 6/30 mg 8/40 mg/mL 0.75 270 courses.247,360,361 For upper respiratory tract disease, long-term 11 18/90 mg 8/40 mg/mL 2.25 300 12 60/300 mg 8/40 mg/mL 7.5 330 aspirin desensitization was associated with significant im- provements in nasal symptom scores, frequency of sinusitis, a Concentrations can be made by making 3 sequential 10-fold dilu- need for polypectomies or sinus operations, sense of smell, tions from the pediatric trimethoprim-sulfamethoxazole (TMP-SMX) and dose of intranasal corticosteroids.247,360,361 For lower re- solution available as 40/200/5 mL (8/40 mg/mL). spiratory tract disease, improved clinical outcomes included reductions in asthma symptom scores, hospitalizations, emer- gency department visits, and dose of inhaled corticoste- E. Pharmacologic Induction of Drug Tolerance (eg, roids.247,360,361,365 Long-term aspirin desensitization also re- Aspirin Desensitization) sulted in a reduction in the number of bursts of oral Summary Statement 68: Pharmacologic induction of drug corticosteroids and allowed patients taking long-term corti- tolerance to aspirin (eg, aspirin desensitization) is primarily costeroids to decrease their dose.247,360,361 intended for patients with aspirin-exacerbated respiratory dis- In contrast to the aforementioned 2- to 4-day protocols for ease (AERD), and unlike other types of desensitization, its induction of drug tolerance to aspirin (aspirin desensitization) purpose is to cautiously induce (rather than prevent) a reac- in patients with AERD, there are limited data on more rapid tion, after which patients become tolerant of aspirin and (2-5 hours) protocols in patients with histories predominantly NSAIDs. (B) of cutaneous reactions (urticaria or angioedema) to aspirin Aspirin desensitization is a form of pharmacologic induc- but also including a few patients with histories of respiratory tion of drug tolerance. Similar to other induction of drug reactions.364-367 Although generally successful for most pa- tolerance procedures, pharmacologic induction of drug toler- tients, patients with chronic urticaria or angioedema that is ance procedures induce a temporary state of tolerance to exacerbated by aspirin do not achieve tolerance via either aspirin that is maintained only as long as the patient continues rapid (2-5 hours) or standard (2-4 days) aspirin challenge or to take aspirin. After aspirin desensitization, loss of tolerance desensitization protocols and continue to experience flares of generally returns in 2 to 4 days after discontinuation of their cutaneous condition with exposure to aspirin or cross- continuous aspirin therapy.359 Pharmacologic induction of drug tolerance is typically performed in hours to days and generally starts with milli- Table 10. Ten-Day Trimethoprim-Sulfamethoxazole Induction of gram amounts. It is commonly used for patients with AERD Drug Tolerance Procedure680a (see section VII.R). The protocol differs from both IgE and Day Dosage, mg Concentration/tablet Amount non-IgE induction of drug tolerance. It involves a metabolic shift, reduction in urinary leukotriene E4, internalization of 1 0.4/2 0.4/2 mg/mL 1 mL cysteinyl 1 receptors, and, in some re- 2 0.8/4 0.4/2 mg/mL 2 mL 3 1.6/8 0.4/2 mg/mL 4 mL ports, release of mast cell tryptase. Precautions for aspirin 4 3.2/16 0.4/2 mg/mL 8 mL desensitization should emphasize frequent monitoring of lung 5 8/40 8/40 mg/mL 1 mL function and management of severe bronchospasm along with 6 16/80 8/40 mg/mL 2 mL those used for other forms of induction of drug tolerance. 7 32/160 8/40 mg/mL 4 mL The most commonly cited and tested protocol (Table 11) 8 64/320 8/40 mg/mL 8 mL involves incremental oral administration of aspirin during 2 9 80/400 80/400-mg tablet 1 tablet to 4 days, starting at 15 to 30 mg and going to 650 10 160/800 160/800-mg tablet 1 tablet 247,360,361 mg. Table 12 depicts a more practical protocol; how- a The 0.4/2-mg/mL concentration can be made by making a 1:20 ever, there are no data on the safety and efficacy of this dilution of the pediatric Trimethoprim-sulfamethoxazole solution protocol. Continued daily administration of 325 to 650 mg of available as 40/200/5 mL (8/40 mg/mL).

VOLUME 105, OCTOBER, 2010 273.e40 Table 11. Aspirin Induction of Drug Tolerance Scripps Protocol681 Table 12. Aspirin Induction of Drug Tolerance, Aspirin Ͼ Ͼ Desensitization Joint Task Force Recommendations682a Assessment and FEV1 60% predicted ( 1.5 L) Ͼ premedication (1-7 days Start or continue treatment with Assessment and FEV1 70% predicted before procedure) , 10 mg daily premedication (within Consider starting or continuing Start or continue treatment with 1 week before leukotriene modifier therapy inhaled corticosteroid and procedure) Start or continue treatment long-acting ␤- with high-dose inhaled Systemic steroid burst if low corticosteroid and long- ␤ FEV1 or bronchial instability acting -agonist if poorly controlled asthma Protocol Systemic steroid burst if low

Time Aspirin Dose FEV1 or bronchial instability If receiving maintenance Day 1: 0 30 mg systemic steroids, consider Day 1: 3 hours 60 mg doubling daily dose (if on Day 1: 6 hours 100 mg alternate day steroids Day 2: 0 150 mg change to daily dose) Day 2: 3 hours 325 mg Day 2: 6 hours 650 mg Protocol Start intravenous catheter with heparin lock (keep in for 2-3 Time Aspirin Dose days). 0 20.25 mg FEV and clinical assessment every hour and with symptoms. 1 90 min 40.5 mg Reactions typically occur with a provoking dose of 20-101mg. 180 min 81 mg Treat with medications described below. Chance of reaction 270 min 162.5 mg to repeated threshold dose is small, but if occurs, repeat dose 360 min 325 mg until reactions cease and then proceed. After patient completely stabilized, provoking dose can be Document informed consent and advise patient it may take repeated (assuming another 3 hours of observation time), several days to complete (most will take 2 days). otherwise start with provoking dose on day 2. Establish intravenous access.

If nasal, gastrointestinal, or cutaneous reactions occur on day 1, FEV1 and clinical assessment every 90 minutes and with pretreat with histamine1 and histamine2 receptor antagonists symptoms. for remainder of procedure. Dosing interval may be extended to 3 hours based on individual patient characteristics. Medications for treatment of aspirin-induced reactions Reactions will likely occur with early doses, usually 81mg. Ocular Topical antihistamines Treat reactions as indicated below. Nasal Antihistamine, topical After patient completely stabilized (but not less than 3 hours Laryngeal Racemic epinephrine nebulization after the last dose), the provoking dose can be repeated. Ͼ Bronchial ␤- A persistent 15% decrease in FEV1, with or without associated symptoms, lasting longer than 3 hours despite Gastrointestinal Histamine2-receptor antagonists Urticaria/angioedema Antihistamine therapy, is an indication to discontinue the desensitization Hypotension Epinephrine process for the day. If nasal, gastrointestinal, or cutaneous reactions occur on day 1, Abbreviation: FEV1, forced expiratory volume in 1 second. pretreat with histamine1 and histamine2 receptor antagonists for remainder of procedure. Medications for treatment of aspirin-induced reactions reacting NSAIDs.366 Although these protocols have been as- sociated with success in allowing patients who otherwise Ocular Oral antihistamines Nasal Oral antihistamine, topical decongestant would have been denied the benefits of aspirin to receive this Laryngeal Racemic epinephrine nebulization and/or drug safely, it is unclear whether these protocols truly induce intramuscular epinephrine drug tolerance (desensitization) or are simply a multistepped Bronchial ␤-Agonists graded-dose challenge. Most of the patients described in Urticaria/angioedema Oral or intravenous antihistamines these reports required aspirin for acute coronary syndromes Hypotension Parenteral epinephrine or before coronary stents and had a history of prior adverse Abbreviation: FEV1, forced expiratory volume in 1 second. reaction to aspirin. No confirmatory challenge studies could a This recommended protocol is intended to be more practical, using be performed to determine whether the previous reactions doses based on commercially available 81 mg aspirin products and a were causally or coincidentally associated with aspirin. For shorter dosing interval. There are no data on safety and efficacy of this reason, it is uncertain whether these patients were truly this protocol. aspirin sensitive. An example of a rapid aspirin challenge desensitization protocol is provided in Table 13.

273.e41 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Table 13. Rapid Aspirin Challenge/Desensitization Protocol for Table 15. Allopurinol (High-Risk Patients) Induction of Drug Patients With Requiring Aspirin366 Tolerance Procedurea Timea Aspirin dose, mg Daily dose Concentration/tablet Amount Days

0 0.1 10 ␮g 1 mg/5 mL 0.05 mL 1-7 15 0.3 25 ␮g 1 mg/5 mL 0.12 mL 8-14 30 1 50 ␮g 1 mg/5 mL 0.25 mL 15-21 45 3 100 ␮g 1 mg/5 mL 0.5 mL 22-28 60 10 200 ␮g 1 mg/5 mL 1 mL 29-35 75 20 500 ␮g 1 mg/5 mL 2.5 mL 36-42 90 40 1 mg 1 mg/5 mL 5 mL 43-49 105 81 5 mg 10 mg/5 mL 2.5 mL 50-56 120 162 10 mg 10 mg/5 mL 5 mL 57-63 135 325 25 mg 10 mg/5 mL 12.5 mL 64-70 50 mg 100-mg tablet ½ tablet 71-77 a Dosing interval shown is 15 minutes but may also dose every 20 100 mg 100-mg tablet 1 tablet Ն78 minutes with premedication with oral antihistamine. a High-risk patients were frail, elderly patients with multiple medical comorbid diseases, renal impairment, or more widespread eruptions, F. Undefined Induction of Drug Tolerance particularly if associated with fever. Summary Statement 69: Some induction of drug tolerance procedures have been described that appear to be successful 368 through currently undefined mechanisms. (C) induce a severe reaction. Although it is not possible to be Some induction of drug tolerance procedures have been absolutely certain that a patient is not allergic to a drug reported for other drugs, but the mechanism of the adverse because valid diagnostic tests are not available for most reaction to the drug and the mechanism of drug tolerance drugs, the procedure is intended for patients who, after a full remains undefined. An example is the procedures (Tables 14 evaluation, are unlikely to be allergic to the given drug. The and 15) used to induce drug tolerance in patients with histo- starting dose for a graded challenge is higher than for induc- ries of cutaneous reactions to allopurinol. Although largely tion of drug tolerance, and the number of steps in the proce- successful, these protocols have been associated with the dure may be 2 or several. It is possible that a “graded subsequent development of significant adverse reactions. challenge” consisting of more than 4 or 5 steps may induce modifications of immune effector cells and therefore induce G. Graded Challenge drug tolerance in the patient. For that reason, future admin- Summary Statement 70: The objective of a graded chal- istrations of the drug should be given cautiously. The inter- lenge is to cautiously introduce a drug in patients who are vals between doses are dependent on the type of previous unlikely to be allergic to it. Unlike induction of drug toler- reaction, and the entire procedure may take hours or days to ance, it does not modify patients’ response to a drug. (D) complete. Because parenteral administration of a drug is Graded challenge (also known as test dosing), unlike in- more likely to produce severe anaphylaxis than oral admin- duction of drug tolerance, does not modify an individual’s istration, more caution should be exercised for graded chal- immune response to a given drug. The objective of a graded lenge procedures that use a parenteral . challenge is to introduce a medication cautiously so as not to One example of when a graded challenge may be appro- priate is in penicillin skin test–positive patients who require treatment with cephalosporins because their reaction rate to Table 14. Allopurinol (Standard Patient) Induction of Drug Tolerance Procedure358a cephalosporins is low (see section VII.A.4). Readministration of a drug via graded challenge is generally contraindicated if Daily dose Concentration/tablet Amount Days it caused a severe non–IgE-mediated reaction, such as SJS, 50 ␮g 1 mg/5 mL 0.25 mL 1-3 TEN, or exfoliative dermatitis. Rare exceptions to this may 100 ␮g 1 mg/5 mL 0.5 mL 4-6 exist, such as treatment of a life-threatening illness, in which 200 ␮g 1 mg/5 mL 1 mL 7-9 case the benefit of treatment outweighs the risk of a poten- 500 ␮g 1 mg/5 mL 2.5 mL 10-12 tially life-threatening reaction. 1 mg 1 mg/5 mL 5 mL 13-15 5 mg 10 mg/5 mL 2.5 mL 16-18 VII. SPECIFIC DRUGS 10 mg 10 mg/5 mL 5 mL 19-21 Almost any drug is capable of inducing an allergic reac- 25 mg 10 mg/5 mL 12.5 mL 22-24 tion and the likelihood that this will occur increases in di- 50 mg 100-mg tablet ½ tablet 25-27 rect proportion to the use pattern of a drug in the general 100 mg 100-mg tablet 1 tablet Ն28 population. a Standard patient had a history of pruritic, erythematous exanthem Drugs differ, however, with their propensities to induce after initiation of allopurinol with resolution of rash after drug therapy either restricted or heterogeneous immune responses within discontinuation. the Gell-Coombs spectrum of human hypersensitivity. This

VOLUME 105, OCTOBER, 2010 273.e42 section will discuss several of the most common clinical Summary Statement 82: Patients who have had negative entities of drug hypersensitivity, some as representative ex- skin test results to penicillin major and minor determinants amples of each of the 4 major Gell-Coombs categories of may receive penicillin with minimal risk of an IgE-mediated human hypersensitivity and others with heterogeneous and reaction. Depending on the reaction history, the first dose often unclassifiable immune characteristics. may need to be given via graded challenge. (D) Summary Statement 83: Penicillin skin test–positive pa- ␤ A. -Lactam Antibiotics tients should avoid penicillin, but if they develop an absolute 1. Penicillin need for penicillin, rapid induction of drug tolerance may be Summary Statement 71: Approximately 10% of patients performed. (B) report a history of penicillin allergy, but after complete eval- Summary Statement 84: Resensitization after treatment uation, up to 90% of these individuals are able to tolerate with oral penicillin is rare, and therefore penicillin skin penicillins. (B) testing does not routinely need to be repeated in patients with Summary Statement 72: Treatment of patients assumed to a history of penicillin allergy who have tolerated 1 or more be penicillin allergic with alternate broad-spectrum antibiot- courses of oral penicillin. (B) ics may compromise optimal medical care by leading to Summary Statement 85: Resensitization after treatment multiple drug-resistant organisms, higher costs, and increased with parenteral penicillin appears to be higher than for oral toxic effects. (C) treatment, and therefore repeat penicillin skin testing may be Summary Statement 73: Evaluation of patients with peni- considered in patients with a history of penicillin allergy who cillin allergy by skin testing leads to reduction in the use of have tolerated a course of parenteral penicillin. (C) broad-spectrum antibiotics and may decrease costs. (B) Summary Statement 86: The negative predictive value of Summary Statement 74: The rate of penicillin-induced penicillin skin testing without penicilloylpolylysine is poor anaphylaxis after parenteral administration is about 1 to 2 per because many allergic patients show skin test reactivity only 10,000 treated patients. (C) to the major determinant. (B) Summary Statement 75: Penicillin is immunologically inert Summary Statement 87: When penicillin skin testing is and haptenates proteins after undergoing spontaneous con- unavailable, evaluation of penicillin allergy is based on the version under physiologic conditions to reactive intermedi- reaction history and likelihood of needing treatment with ates. These transformation products are known as penicillin penicillins. (C) major and minor antigenic determinants. (C) Summary Statement 88: Patients with a vague and/or dis- Summary Statement 76: Penicillin skin testing is the most tant history of penicillin allergy may be candidates to receive reliable method for evaluating IgE-mediated penicillin al- penicillins via graded challenge. Patients with recent or con- lergy. (B) Ideally, penicillin skin testing should be performed vincing reaction histories should only receive penicillins via with both major and minor determinants. The negative pre- rapid induction of drug tolerance. (C) dictive value of penicillin skin testing for immediate reactions Summary Statement 89: The usefulness of in vitro tests for approaches 100%, whereas the positive predictive value is penicillin specific IgE is limited by their uncertain predictive value. They are not suitable substitutes for penicillin skin between 40% and 100%. (B) testing. (C) Summary Statement 77: Skin testing with the major deter- Approximately 10% of patients report a history of reacting minant and penicillin G only (without penicilloate and pe- to a penicillin class antibiotic. When evaluated for penicillin nilloate) may miss up to 20% of allergic patients, but data on allergy, up to 90% of these individuals are able to tolerate this are conflicting. (C) penicillins and therefore are designated as being penicillin Summary Statement 78: Penicillin G left in solution allergic unnecessarily.17,18,369 There are several explanations (“aged” penicillin) does not spontaneously degrade to form to account for this discrepancy. Penicillin specific IgE anti- antigenic determinants and has no role in penicillin skin bodies are known to rapidly wane over time.370 It is likely that testing. (B) some reactions, particularly cutaneous eruptions, were the Summary Statement 79: Penicillin skin testing without the result of an underlying viral or bacterial infection or an major determinant is not recommended because this would interaction between the infectious agent and the antibiotic.371,372 fail to identify many patients with penicillin specific IgE Some patients may mislabel the antibiotic they were treated antibodies. (B) with as penicillin or may attribute predictable reactions (ie, Summary Statement 80: When performed by skilled per- diarrhea or ) as allergic. sonnel using proper technique, serious reactions due to pen- Although most patients with a history of penicillin al- icillin skin testing are extremely rare. (C) lergy could tolerate penicillin, clearly there is potential Summary Statement 81: Penicillin skin testing may be for serious and life-threatening immediate-type reactions to performed electively—when patients are well and not in penicillin if it is readministered.302 For this reason, physicians immediate need of antibiotic therapy. Alternatively, penicillin are faced with antibiotic choices that may be less effective, skin testing may be performed when treatment with a peni- more toxic, or more expensive and may compromise optimal cillin compound is contemplated. (D) medical care.19,373-377 In addition, in the era of multiple anti-

273.e43 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY microbial drug resistance, the use of broad-spectrum antibi- with vague reaction histories may be allergic and demonstrate otics in patients designated as being penicillin allergic aug- positive skin test results.375,391,392 Overall, approximately one- ments this problem.19,374,378,379 A number of medical centers third of patients with positive penicillin skin test results report have used penicillin skin testing (many using only penicil- vague reaction histories.393 Penicillin skin testing is the most loylpolylysine and penicillin G as skin test reagents) in pa- reliable method for evaluating IgE-mediated penicillin al- tients with a history of penicillin allergy to reduce the use of lergy. In vitro tests ( or enzyme- broad-spectrum antibiotics and improve use of antibiotic linked ) are less sensitive and specific compared selections.377,380-384 with skin testing.394 Penicillin skin testing detects the pres- There are few prospective data on the rate of penicillin ence or absence of penicillin specific IgE antibodies, and it is sensitization. Among military recruits without a history of not useful or indicated for clearly non–IgE-mediated reactions. penicillin allergy, 51 of 614 patients (8.2%) converted from a Ideally, both major and minor determinant reagents are negative to positive penicillin skin test result (using penicil- used for skin testing. The major determinant has been com- loylpolylysine as the only reagent) after a single injection of mercially available as penicilloylpolylysine (PRE-PEN) in a benzathine penicillin G.385 Most penicillin class antibiotic premixed 6 ϫ 10Ϫ5M solution. Of the minor determinants, reactions involve cutaneous eruptions, and in a large-scale penicillin G is commercially available and should be used for review of adverse skin reactions of the Boston Collaborative skin testing at a concentration of 10,000 U/mL. The other Drug Surveillance Program, the frequency of skin reactions minor determinants (penicilloate and penilloate) are used for was 5.1% with amoxicillin, 4.5% with ampicillin, and 1.6% skin testing at 0.01M but have never been commercially 305 with penicillin. Most of these reactions were macular, available in the United States. Penicillin G left in solution morbilliform, or urticarial, and it is unclear how many were (“aged” penicillin) does not spontaneously degrade to form IgE dependent. Life-threatening anaphylactic reactions to other minor determinants and therefore cannot be used as a penicillin are of the most concern, and they appear to be rare. substitute for the other minor determinants.395 The negative In 1968, in a review of published and unpublished reports, the predictive value of penicillin skin testing (using penicilloyl- rate of penicillin-induced anaphylaxis was 0.015% to 0.04% 302 polylysine, penicillin G and penicilloate, and/or penilloate) of treated patients. In a study of children and young adults for serious immediate-type reactions approaches 100%,17,18,396 receiving monthly injections of benzathine penicillin G for an and the positive predictive value (based on limited challenges average of 3.4 years, the incidence of anaphylaxis was 1.23 of skin test–positive patients) is between 40% and 100%.17,396,397 per 10,000 injections, but none occurred in the 600 patients Because penicilloate and penilloate have never been com- younger than 12 years.386 Among healthy military recruits, 2 mercially available in the United States, most allergists per- of 9,203 experienced anaphylaxis after prophylactic treat- form penicillin skin tests with only penicilloylpolylysine and ment with a single dose of benzathine penicillin (ie, 2.17 per 10,000).387 penicillin G. However, some studies report that approxi- mately 10% to 20% of penicillin-allergic patients show skin Penicillin is chemically inert in its native state and can only 17,18,391,398 haptenate proteins after undergoing conversion to reactive test reactivity only to penicilloate or penilloate. The intermediates. This process occurs spontaneously under phys- clinical significance of these findings is uncertain. Penicillin challenges of individuals skin test negative to penicilloyl- iologic conditions, whereas most other antibiotics must be 397,399 metabolized enzymatically to produce intermediates capable polylysine and penicillin G have similar reaction rates of binding to host proteins. The penicillin molecule has a core compared with individuals skin test negative to the full set of 17,18,396 bicyclic structure composed of a 4-member ␤-lactam ring and major and minor penicillin determinants. Therefore, a 5-member thiazolidine ring. Under physiologic conditions, based on the available literature, skin testing with penicilloyl- the ␤-lactam ring opens spontaneously, allowing the carbonyl polylysine and penicillin G appears to have adequate negative group to form an amide linkage with amino groups of predictive value in the evaluation of penicillin allergy. residues on nearby proteins.388,389 This penicilloyl group com- Penicillin skin testing should only be performed by per- prises approximately 95% of the tissue-bound penicillin and sonnel skilled in the application and interpretation of this type therefore is called the major antigenic determinant. The re- of skin testing, with preparedness to treat potential anaphy- maining portion of penicillin either remains in the native state laxis.400 Appropriate positive (histamine) and negative (sa- or degrades further to a variety of minor antigenic determi- line) controls should be placed. First, full-strength reagents nants capable of haptenating proteins. The most important of are applied by the prick/puncture technique, and if these these are penicilloate and penilloate, and they, along with results are negative, intradermal testing should be performed. penicillin itself, cover all clinically relevant allergenic deter- There is no uniform agreement on what constitutes a positive minants not covered by penicilloyl and are not cross-reactive skin test response, but most experts agree that it is defined by with one another.390 the size of the wheal, which should be 3 mm or greater than Immediate-type penicillin allergy cannot be accurately di- that of the negative control for either prick/puncture or intra- agnosed by history alone. This observation is partially ex- dermal tests. Penicillin skin testing, using the reagents de- plained by the fact that patients with convincing reaction scribed above and proper technique, are safe with only a rare histories lose their sensitivity over time. In addition, patients risk of a systemic reactions occurring.18,401

VOLUME 105, OCTOBER, 2010 273.e44 Penicillin skin testing appears to sensitize a small percent- including after repeated courses.369,380,405,406 Hence, routine age of patients. Of 239 patients with initially negative peni- repeat penicillin skin testing is not indicated in patients with cillin skin test results, 6 patients (2.5%) converted to a pos- a history of penicillin allergy who have tolerated 1 or more itive skin test 1 month later (without any treatment with oral courses of oral penicillin. Consideration may be given penicillin).402 The clinical significance of this skin test con- to retesting individuals with recent or particularly severe version is unknown because none of the patients were sub- previous reactions. Resensitization after high-dose parenteral sequently challenged with penicillin. In a previous study, treatment with penicillin appears to be more likely; there- among 614 patients without a history of penicillin allergy, 51 fore, repeat penicillin skin testing in this situation may be (8.2%) converted from a negative to positive skin test result warranted.407,408 (using penicilloylpolylysine as the only reagent) after a single The approach to evaluation of penicillin allergy in the injection of penicillin G.385 Each of these 51 patients was then absence of penicilloylpolylysine is different compared with given a second injection of penicillin G and none experienced when the major determinant is available. Omission of peni- a reaction. cilloylpolylysine from the penicillin skin testing panel results Penicillin skin testing is indicated in patients who have a in a failure to identify many penicillin-allergic individuals. reaction history consistent with a possible IgE-mediated Depending on the population studied, as many as 75% of mechanism. Penicillin skin testing may be performed elec- penicillin skin test–positive patients showed positive re- tively (when patients are well and not in immediate need of sponses to only penicilloylpolylysine.18,398,409 As a result, the antibiotic therapy) or only when treatment with a penicillin negative predictive value of penicillin skin testing without compound is contemplated. Arguments in favor of elective penicilloylpolylysine is poor, and, in that situation, elective skin testing include the fact that penicillin skin testing in the penicillin skin testing is not recommended. Also, in remote acute setting when a patient is ill is more difficult to accom- areas, clinicians may not have access to an allergist/immu- plish in a timely fashion. Consequently, such patients are nologist to perform penicillin skin testing even if appropriate treated with alternate antibiotics,19,374,376,393 many of which, reagents are available. such as vancomycin and fluoroquinolones, have a broader Without penicillin skin testing, the approach to patients spectrum of antimicrobial activity or may be more toxic or with a history of penicillin allergy is based on the reaction expensive. Overuse of broad-spectrum antibiotics is known to history and likelihood of needing treatment with penicillins. contribute to the development and spread of multiple antibi- One such group of patients is those who report reactions to otic resistance.378,379,403 Arguments in favor of testing at time many different classes of antibiotics and thus are “running of need include the potential of skin testing or the subsequent out” of antibiotic choices. Patients with convincing reaction course of penicillin (in skin test–negative individuals) to histories are more likely to be allergic than patients with induce resensitization and hence the need to repeat penicillin vague reaction histories.18,397,410,411 However, as discussed - skin testing before each future course. lier, vague reaction histories cannot be completely discounted There is lack of agreement regarding the need, immedi- because those patients may also be penicillin allergic.375,391,392 ately after a negative penicillin skin test result, to perform an The time elapsed since the reaction is useful because peni- elective challenge with penicillin. Surveys of patient with cillin specific IgE antibodies wane over time, and therefore negative penicillin skin test results (without subsequently patients with recent reactions are more likely to be allergic being challenged with penicillin) found that a large propor- than patients with distant reactions. Approximately 50% of tion was not treated with ␤-lactam antibiotics because of fear patients with IgE-mediated penicillin allergy lose their sen- on either the part of the patient or the treating physician.404 In sitivity 5 years after reacting, and this percentage increases to an enclosed health maintenance organization setting, review approximately 80% in 10 years.370,412 Recently, a study of 169 of medical records found that subsequent prescriptions for patients with a non–life-threatening history of penicillin al- penicillins in penicillin skin test–negative patients were com- lergy and who had avoided penicillin for more than 3 years parable in those individuals who were and were not chal- were evaluated by penicillin skin tests with major and minor lenged with oral penicillin after their skin test (47% vs 48% determinants and graded challenge, regardless of whether the during the year after the skin test).380 If penicillin skin testing penicillin skin test result was positive or negative.413 A low is performed with only penicilloylpolylysine and penicillin G, rate of positive penicillin challenges occurred in both groups, initial administration of penicillin, depending on the pretest which was not statistically different (6.6% in the penicillin probability of the patient being allergic, may need to be done skin test–positive group and 3.7% in the penicillin skin test– via graded challenge (ie, 1/100 of the dose, followed by the negative group). This study suggests that penicillin specific full dose, assuming no reaction occurs during a brief obser- IgE in some patients may indicate sensitization rather than vation period). true clinical allergy. Patients with distant (longer than 10 Several studies have addressed the issue of resensitization years) or questionable reaction histories (eg. vague childhood (ie, redevelopment of penicillin allergy) in patients with a rash), due to their relatively low likelihood of being penicillin history of penicillin allergy who later demonstrate negative allergic, may be candidates to receive penicillin via graded penicillin skin test results. Resensitization after oral treatment challenge, as opposed to induction of drug tolerance proce- with penicillin is rare in both pediatric and adult patients, dure. In contrast, if there is a convincing history of an

273.e45 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY IgE-mediated reaction to penicillin (eg. anaphylaxis), partic- patients with Epstein-Barr virus infections, almost 100% will ularly if the reaction was recent, penicillin should be admin- develop a nonpruritic rash.371,372 The incidence of nonpruritic, istered via induction of drug tolerance procedure. Clinical cutaneous reactions also may be increased in patients who judgment is required to carefully weigh the risks and benefits have an elevated uric acid, are being treated with allopurinol, of either procedure and informed consent (verbal or written) or have chronic lymphocytic .420,421 Because pa- of the patient in determining which type of procedure is in the tients’ reaction histories are known to be a poor predictor of patient’s best interest. skin test results,375,392 penicillin skin testing should be con- In vitro tests for IgE directed against penicilloylpolylysine, sidered even in patients with a history suggestive of amoxi- penicillin G, penicillin V, amoxicillin, and ampicillin are cillin/ampicillin-associated maculopapular rashes before a fu- commercially available, but they are not suitable alternatives ture course of penicillin is given. If the penicillin skin test to skin testing because these assays have unknown predictive result is negative, the patient should be approached as out- value, which limits their usefulness. When performed in lined in the prior discussion about penicillin. If the penicillin academic settings, the sensitivity of in vitro tests for penicil- skin test result is positive, the patient should be given an lin specific IgE was as low as 45% compared with skin alternative antibiotic or undergo induction of drug tolerance testing.414,415 A positive penicillin in vitro test result in the to penicillin. context of an appropriate reaction history suggests presence 3. Cephalosporins (Figure 2) of an IgE-mediated allergy; however, a negative in vitro test Summary Statement 92: The overall reaction rate to ceph- result does not rule out an IgE-mediated allergy. alosporins is approximately 10-fold lower than it is for pen- 2. Ampicillin and Amoxicillin icillin. (C) Summary Statement 90: Some patients with immediate- Summary Statement 93: Most hypersensitivity reactions to type reactions to amoxicillin and ampicillin have IgE anti- cephalosporins are probably directed at the R-group side bodies directed at the R-group side chain (rather than the core chains rather than the core ␤-lactam portion of the molecule. penicillin determinants) and are able to tolerate other peni- (D) cillin class compounds. (C) Summary Statement 94: Skin testing with native cephalo- Summary Statement 91: Amoxicillin and ampicillin are sporins is not standardized, but a positive skin test result associated with the development of a delayed maculopapular using a nonirritating concentration suggests the presence of rash in approximately 5% to 10% of patients. (C) These drug specific IgE antibodies. (D) A negative skin test result reactions are not related to IgE-mediated allergy, and they are does not rule out an allergy because the negative predictive postulated in many cases to require the presence of a concur- value is unknown. (D) rent viral infection or another underlying illness. (D) Summary Statement 95: Patients with a history of an im- Some patients with immediate-type reactions to amoxicil- mediate-type reaction to 1 cephalosporin should avoid ceph- lin or ampicillin are able to tolerate other penicillin class alosporins with similar R-group side chains. (D) Treatment compounds.416-418 These individuals appear to have reactions with cephalosporins with dissimilar side chains may be con- directed at the R-group side chain, which distinguishes the sidered, but the first dose should be given via graded chal- chemical structure of different penicillin class compounds. lenge or induction of drug tolerance, depending on the sever- These patients may have skin test results that are positive to ity of the previous reaction. (D) a nonirritating concentration of either amoxicillin or ampicil- Summary Statement 96: Cephalosporins and penicillins lin but test negative to penicillin major and minor determi- share a common ␤-lactam ring structure and moderate cross- nants.416-418 Therefore, skin testing of patients who have reactivity has been documented in vitro. (B) reacted to semisynthetic penicillins with the implicated anti- Overall, the rate of allergic reactions to cephalosporins is biotic and penicillin major and minor determinants may add approximately 10-fold lower than it is to penicillin.422 Anec- additional useful information. The negative predictive value dotal evidence suggests that allergic reactions to cephalospo- of skin testing with native semisynthetic penicillins is un- rins are directed at the R-group side chains rather than the known, and there is no consensus regarding the appropriate core ␤-lactam portion of the molecule.423-427 However, there concentration that should be used. are no clinical challenge studies to prove that patients allergic Administration of ampicillin and amoxicillin is associated to one cephalosporin are able to tolerate other cephalosporins with the development of a delayed maculopapular rash in 5% with dissimilar side chains. If a patient with a history of to 10% of patients.419 These patients are not at risk of a allergy to one cephalosporin requires treatment with another life-threatening immediate reaction to penicillin. Most pa- cephalosporin, the following approach may be considered: tients will tolerate future administration of penicillin other (1) after ensuring that 2 cephalosporins do not share R-group than ampicillin and amoxicillin. If ampicillin or amoxicillin is side chains, perform a graded challenge with the new ceph- administered again, the patient may develop a similar erup- alosporin; (2) perform cephalosporin skin testing (with the tion or no reaction at all. It is postulated that many amoxi- agent to be used), although such skin testing is not standard- cillin/ampicillin-associated delayed maculopapular rashes re- ized and the negative predictive value is unknown; or (3) quire the presence of a concurrent viral illness. In the case of perform cephalosporin induction of drug tolerance, particu-

VOLUME 105, OCTOBER, 2010 273.e46 Figure 2. Cephalosporin algorithms.

273.e47 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY larly if there is a history of severe anaphylaxis Ten-fold Summary Statement 102: Skin testing to the cephalosporin dilutions of native cephalosporins have been reported to be followed by graded challenge appears to be a safe method for nonirritating,428 but each cephalosporin may require concur- administration of some cephalosporins in penicillin allergic rent evaluation for its potential in nonallergic pa- patients. (B) tients. Skin testing should be performed as described in the Summary Statement 103: If penicillin and cephalosporin penicillin section with a prick/puncture test followed by an skin testing is unavailable, depending on the reaction history, intracutaneous test (if the prick-test reaction is negative in 10 cephalosporins may need to be given via graded challenge or to 15 minutes). If the previous clinical reaction was docu- rapid induction of drug tolerance. (E) mented as anaphylactic and life-threatening, testing should Cephalosporins and penicillins have a common ␤-lactam start at a further 10-fold dilution or lower. A positive ceph- ring structure and moderate cross-reactivity has been docu- 429-431 alosporin skin test result (using a nonirritating concentration) mented in vitro. Most of the in vitro cross-reactions implies the presence of drug specific IgE antibodies, and the between penicillins and cephalosporins have involved first- 429-431 patient should receive an alternate drug or undergo induction and second-generation cephalosporins. Although clini- of drug tolerance. A negative cephalosporin skin test (using a cally significant cross-reactivity between penicillin and the nonirritating concentration) does not rule out the presence of cephalosporins is infrequent, anaphylactic reactions after ad- ministration of cephalosporin have occurred in patients with drug specific IgE antibodies. IgE antibodies to cephalosporin 23,432-436 degraded products not used in the testing may be present but a history of penicillin allergy. Before 1980, penicillin allergy history–positive and skin test–positive patients who not detectable. Therefore, because the negative predictive were given cephalosporins had a reaction rate of approxi- value of cephalosporin skin testing is unknown, a cautious mately 10% to 20%.430,437 Since 1980, reaction rates in pen- graded challenge should be performed (eg, 1/100 of the icillin history–positive and skin test–positive patients treated therapeutic dose, increasing 10-fold every 30 to 60 minutes with cephalosporins have decreased to 2%.22,438-440 Before up to the full therapeutic dose). The number of steps in the 1980, all penicillin allergic patients who reacted to a cepha- graded challenge and the pace of the challenge are deter- losporin had been treated with cephalothin or . mined by the reaction history. Graded challenges require may Benzyl penicillin and these cephalosporins share a similar be performed in an outpatient setting, without intravenous side chain, a finding that could account for increased cross- access, but with preparedness to treat severe allergic reac- reactivity. Also, during this time, some early first-generation tions, such as anaphylaxis. If the previous history is consis- cephalosporins were contaminated with trace amounts of tent with a severe IgE-mediated reaction, induction of drug penicillin.441 Since 1980, contamination of this type has not tolerance with the cephalosporin may be undertaken instead. been documented. 4. Cephalosporin Administration to Patients With a If patients with a history of allergy to penicillin are not skin History of Penicillin Allergy (Figure 2) tested but given cephalosporins directly, the chance of a Summary Statement 97: Since 1980, studies show that reaction is probably less than 1%. This figure is based on the approximately 2% of penicillin skin test–positive patients fact that only approximately 10% of penicillin history–posi- tive patients have positive skin test results,17,18 and of those, react to treatment with cephalosporins, but some of these only 2% will react to a cephalosporin.22,438-440 This finding reactions may be anaphylactic reactions. (C) may be interpreted to mean that skin testing is unnecessary Summary Statement 98: Without preceding penicillin skin because a 2% reaction rate may occur even without a prior testing, cephalosporin treatment of patients with a history of history of allergy. However, some of these reactions were penicillin allergy, selecting out those with severe reaction fatal anaphylaxis.23,435 Patients with a history of penicillin histories, show a reaction rate of 0.1% based on recent allergy who have negative skin test results to penicillin using studies. (C) major and minor determinants may receive cephalosporins Summary Statement 99: Penicillin skin testing, when avail- safely.24 able, should be considered before administration of cephalo- Recent retrospective studies of administration of mostly sporins in patients with a history of penicillin allergy. (E) parenteral cephalosporins to patients with a history of peni- Summary Statement 100: Patients who have a history of a cillin allergy, without prior penicillin skin testing, have possible IgE-mediated reaction to penicillin, regardless of the shown only 2 possible cephalosporin allergic reactions severity of the reaction, may receive cephalosporins with among 906 patients, neither of which appeared to be IgE minimal concern about an immediate reaction if skin test mediated.442,443 However, there was probably a selection bias results for penicillin major and minor determinants are neg- in deciding which patients were treated with cephalosporins ative. (B) instead of non–␤-lactam antibiotics. Physicians in these Summary Statement 101: Treatment options for penicillin “real-world” studies were probably less likely to treat with skin test–positive patients include (1) administration of an cephalosporins if patients had more severe or recent reaction alternate (non–␤-lactam) antibiotic, (2) administration of histories, and, in some cases, intervened to pre- cephalosporin via graded challenge, or (3) administration of vent patients with severe reaction histories from receiving cephalosporin via rapid induction of drug tolerance. (E) cephalosporins.443

VOLUME 105, OCTOBER, 2010 273.e48 ␤ a Table 16. Groups of -Lactam Antibiotics That Share Identical R1-Group Side Chains Amoxicillin Ampicillin Ceftazidime Cefadroxil Cefaclor Cephaloridine Aztreonam Cefprozil Cephalexin Cephalothin Cefatrizine Cephradine Cephaloglycin Loracarbef a Each column represents a group with identical R1 side chains.

It is also possible that some patients with a history of fadroxil.444,445 Therefore, amoxicillin allergic patients should penicillin allergy react to cephalosporins because of their avoid cephalosporins with identical R-group side chains (ce- underlying propensity to develop reactions to unrelated drugs fadroxil, cefprozil, cefatrizine) or receive them via rapid rather than allergic cross-reactivity between the ␤-lactams. In induction of drug tolerance (Table 16). Similarly, ampicillin patients with documented allergic-like reactions to penicil- allergic patients should avoid cephalexin, cefaclor, cephra- lins, the relative risk for allergic-like reactions was elevated dine, cephaloglycin, and loracarbef or receive them via rapid for both cephalosporins and sulfonamides.307 induction of drug tolerance (Table 17). Nevertheless, because of these disparate observations, there is not a common consensus regarding the management 5. Penicillin Administration to Patients With a History of of a patient with a history of an IgE-mediated reaction to Cephalosporin Allergy (Figure 2) penicillin and who subsequently requires administration of Summary Statement 104: Patients allergic to amoxicillin cephalosporin. The following are options that may be con- should avoid cephalosporins with identical R-group side sidered: (1) substitute a non–␤-lactam antibiotic; (2) perform chains (cefadroxil, cefprozil, cefatrizine) or receive them via penicillin skin testing; (3) perform cephalosporin skin test rapid induction of drug tolerance. (C) Similarly, patients and if the result is negative perform a graded challenge; or (4) allergic to ampicillin should avoid cephalosporins/carba- treat with the cephalosporin. The fourth option should be cephems with identical R-group side chains (cephalexin, ce- considered only in the absence of a severe and/or recent faclor, cephradine, cephaloglycin, loracarbef) or receive them penicillin allergy reaction history. If the penicillin skin test via rapid induction of drug tolerance. (C) result is negative, the patient can receive the cephalosporin. If Summary Statement 105: Patients with a history of an the skin test result is positive, there may be a slightly in- immediate-type reaction to a cephalosporin should undergo creased risk of a reaction if the cephalosporin is given and penicillin skin testing, if available, before treatment with cephalosporin should be administered via graded challenge or penicillin. (E) If test results are negative, they may safely rapid induction of drug tolerance. Skin testing to cephalospo- receive penicillins. (B) If test results are positive, an alternate rins may also be considered for patients with a history of drug should be used or they should undergo rapid penicillin penicillin allergy. One study evaluated 128 patients with induction of drug tolerance. (B) If penicillin skin testing is convincing histories of penicillin allergy and confirmed by unavailable, penicillin may be administered via cautious positive penicillin skin test results.22 Of these 128 subjects, 114 had negative intracutaneous skin test results to cephalo- graded challenge. (C) sporins at 2 mg/mL, 90 underwent challenges to Patients with a history of an immediate-type allergic reac- and ceftriaxone, and all the results were negative. Therefore, tion to a cephalosporin who require penicillin should undergo particularly in patients with convincing histories for penicillin penicillin skin testing. If results are negative, they can receive allergy who require cephalosporins, skin testing to the ceph- penicillin; if results are positive, they should receive an alosporin followed by graded challenge appears to be a safe alternate drug or undergo penicillin induction of drug toler- method for administration of cephalosporins. ance. If penicillin skin testing is unavailable, because the Allergic cross-reactivity between amoxicillin and cephalo- likelihood of reaction is low, cautious graded challenge with sporins that share identical R-group side chains is higher penicillin may be considered in patients with a history of than for penicillin skin test–positive patients. Twelve per- immediate-type allergy to cephalosporins. If a patient has a cent to 38% of patients proven to be selectively allergic to history of a non–IgE-mediated reaction to cephalosporin amoxicillin (ie, able to tolerate penicillin) reacted to ce- (other than serious reactions such as SJS or TEN) and re-

␤ a Table 17. Groups of -Lactam Antibiotics That Share Identical R2-Group Side Chains Cephalexin Cefotaxime Cefuroxime Cefaclor Cefadroxil Cephalothin Cefoxitin Cefamandole Loracarbef Ceftizoxime Cephradine Cephaloglycin Cephapirin a Each column represents a group with identical R2 side chains.

273.e49 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY quires penicillin, a graded challenge with penicillin may be group of individuals.25 A previous study found that 20 of 40 performed and skin testing is not indicated. penicillin skin test–positive patients were skin test positive to imipenemoyl-polylysine or imipenemoate, and none of them 6. Monobactams (Aztreonam) were challenged with .456 Therefore, penicillin skin Summary Statement 106: Aztreonam is less immunogenic test–negative patients may safely receive carbapenems. Pen- than penicillin and cephalosporins, and clinical allergic reac- ␤ icillin skin test–positive patients and patients with a history of tions to aztreonam are less common than other -lactam penicillin allergy who do not undergo skin testing should antibiotics. (C) receive carbapenems via graded challenge. Summary Statement 107: Aztreonam does not cross-react with other ␤-lactams except for ceftazidime, with which it B. Non–␤-Lactam Antibiotics shares an identical R-group side chain. (B) Summary Statement 109: Any non–␤-lactam antibiotic has Aztreonam is less immunogenic than both penicillin and the potential of causing an IgE-mediated reaction, but these cephalosporins,446 and clinical experience confirms that aller- appear to occur less commonly than with ␤-lactam antibiot- gic reactions to aztreonam appear to be uncommon. Evalua- ics. (C) tion of IgE-mediated allergy to aztreonam is analogous to Summary Statement 110: There are no validated diagnostic cephalosporins in that relevant allergenic degradation prod- tests for evaluation of IgE-mediated allergy to non–␤-lactam ucts are unknown, and thus there are no standardized skin test antibiotics. (C) Evaluation of possible allergy to these anti- reagents available. Skin testing with a nonirritating concen- biotics should be limited to situations when treatment with tration of native aztreonam has the same limitation and ques- the drug is anticipated (rather than electively as for penicil- tionable predictive value as with cephalosporins. lin). (D) In vitro tests, skin tests, and patient challenge studies have Summary Statement 111: Skin testing with nonirritating consistently shown no cross-reactivity between penicillin and concentrations of non–␤-lactam antibiotics is not standard- aztreonam.447-452 Likewise, no cross-reactivity has been dem- ized. A negative skin test result does not rule out the possi- onstrated between cephalosporins and aztreonam, except for bility of an immediate-type allergy. A positive skin test result ceftazidime, which shares an identical R-group side chain suggests the presence of drug specific IgE antibodies, but the with aztreonam.315,446,449 Therefore, penicillin and cephalo- predictive value is unknown. (D) sporin allergic patients may safely receive aztreonam, with Summary Statement 112: Patients with a history of reac- the exception of patients who are allergic to ceftazidime. tions to non–␤-lactam antibiotics consistent with an IgE- Conversely, aztreonam allergic patients may be treated with mediated mechanism should only receive them if an alternate all ␤-lactams except for ceftazidime. agent cannot be substituted and only via rapid induction of drug tolerance. (D) 7. Carbapenems Summary Statement 113: Sulfonamide antibiotics rarely Summary Statement 108: Limited data indicate lack of cause IgE-mediated reactions and more commonly result in significant allergic cross-reactivity between penicillin and delayed maculopapular rashes, particularly in human immu- carbapenems. (B) Penicillin skin test–negative patients may nodeficiency virus–positive patients. (C) safely receive carbapenems. (C) Penicillin skin test–positive Summary Statement 114: There is no evidence to suggest patients and patients with a history of penicillin allergy who allergic cross-reactivity between sulfonamide antibiotics and do not undergo skin testing should receive carbapenems via nonantibiotic sulfonamides. (C) graded challenge. (C) Summary Statement 115: Vancomycin rarely causes IgE- There are no formal studies into the immunogenicity or mediated reactions, but more than 50% of patients experience frequency of allergic reactions to carbapenems. Evaluation of immediate cutaneous erythema, flushing, and pruritus (red IgE-mediated allergy to carbapenems is analogous to that of man syndrome), which is the result of non–IgE-mediated cephalosporins and monobactams. No standardized skin test histamine release. (C) reagents are available, and skin testing with nonirritating Summary Statement 116: Red man syndrome reactions can concentrations of the native antibiotic has questionable pre- be prevented by slowing the rate of infusion and premedicat- dictive value. ing with histamine1 receptor antihistamines. (C) The extent of clinical cross-reactivity between carbapen- Summary Statement 117: Aminoglycosides rarely cause ems and other ␤-lactams appears to be very low. Retrospec- drug allergic reactions, including IgE-mediated systemic re- tive studies of hospitalized patients with a history of penicil- actions. (C) lin allergy (who were not skin tested) showed that Summary Statement 118: IgE-mediated and non–IgE-me- approximately 10% developed possibly allergic reactions diated anaphylactic reactions have been reported with quin- during treatment with carbapenems, and none of these reac- olones. In vitro studies suggest a large extent of allergic tions was life-threatening.453-455 Among penicillin skin test– cross-reactivity among quinolones, but there are no clinical positive patients, 111 of 112 were skin test negative to studies to confirm this. (C) imipenem and all 111 tolerated challenge with imipenem.26 Summary Statement 119: Anaphylactic or anaphylactoid Similar was seen with in this same reactions during the operative and perioperative periods may

VOLUME 105, OCTOBER, 2010 273.e50 Table 18. Nonirritating Concentrations of 15 Antibiotics428 ries, a graded challenge procedure may be considered. Read- Antimicrobial Full-strength Dilution from Nonirritating ministration of drugs that caused severe non–IgE-mediated drug concentration full strength concentration reactions (such as SJS, TEN, and others), by either induction of drug tolerance or graded challenge, is generally contrain- Ϫ4 ␮ 100 mg/mL 10 10 g/mL dicated, with rare exceptions, such as treatment of a life- Cefotaxime 100 mg/mL 10Ϫ1 10 mg/mL Cefuroxime 100 mg/mL 10Ϫ1 10 mg/mL threatening infection in which case the benefit of treatment 330 mg/mL 10Ϫ1 33 mg/mL outweighs the risk of a potentially life-threatening reaction. Ceftazidime 100 mg/mL 10Ϫ1 10 mg/mL Up to 4% of patients treated with sulfonamide antibiotics Ceftriaxone 100 mg/mL 10Ϫ1 10 mg/mL experience allergic reactions.458 The most typical reaction 150 mg/mL 10Ϫ1 15 mg/mL consists of a delayed maculopapular eruption, and type I Cotrimoxazole 80 mg/mL 10Ϫ2 800 ␮g/mL reactions appear to be much less common. HIV-positive Erythromycin 50 mg/mL 10Ϫ3 50 ␮g/mL patients are at greatly increased risk of experiencing cutane- 40 mg/mL 10Ϫ1 4 mg/mL ous reactions to trimethoprim-sulfamethoxazole, and this Ϫ 25 mg/mL 10 3 25 ␮g/mL topic is discussed in more detail in section VII.F. There are Ϫ4 ␮ 250 mg/mL 10 25 g/mL data suggesting that patients with a history of allergy to 200 mg/mL 10Ϫ1 20 mg/mL Tobramycin 80 mg/2 mL 10Ϫ1 4 mg/mL sulfonamide antibiotics are at slightly increased risk of react- Vancomycin 50 mg/mL 10Ϫ4 5 ␮g/mL ing to nonantibiotic sulfonamides, although this does not appear to be due to immunologic cross-reactivity but rather a nonspecific predisposition to react to drugs.27,459,460 Although all sulfonamides contain an NH2-SO2 moiety, sulfonamide be caused by induction agents, muscle relaxing agents, opi- antibiotics also contain an aromatic amine at the N4 position ates, antibiotics, and latex allergy. (C) and a substituted ring at the N1 position, and these groups are Allergic reactions to non–␤-lactam antibiotics can cause believed to be essential for various types of allergic reactions morbidity and, rarely, mortality. The overall incidence of to sulfonamide antibiotics.461-463 hypersensitivity reactions to these agents is estimated to be Vancomycin has been reported to cause drug fever, im- 1% to 3%. Some agents, such as trimethoprim-sulfamethox- mune cytopenias, rash, or a distinctive cutaneous lesion, the azole, are more prone to induce such reactions, particularly in red man syndrome, characterized by pruritus, erythema, and HIV-infected individuals (see section VII.F).457 Because there flushing of the face, neck, and upper chest with occasional are no validated diagnostic tests for allergies to non–␤-lactam hypotension. More than 50% of treated patients experience antibiotics, evaluation of a possible allergy should not be some of these manifestations, although most of them are performed electively but rather be limited to situations when mild. The symptoms are due to non–IgE-mediated histamine treatment with the drug is required and anticipated. release that is probably related to the peak concentration,464 so For most non–␤-lactam antibiotics, there are case reports that slowing the rate of infusion will generally prevent further of positive skin test results with the native drug; however, symptoms. Premedication with an histamine1 receptor anti- large-scale validation of such skin testing has not been ac- histamine also helps to alleviate symptoms.465 IgE-mediated complished. It is well recognized that most antibiotics have anaphylaxis to vancomycin has also been observed and may multiple end products, and therefore it is possible that the be identified by skin tests, but skin tests at concentrations of relevant allergens may be metabolites and not the parent 100 ␮g or greater may elicit false-positive wheal-and-flare drug. Although no validated in vivo or in vitro diagnostic reactions in normal skin.354 Anaphylaxis should be managed tests are available for non–␤-lactam antibiotics, skin testing in the same manner described for other non–␤-lactam anti- with nonirritating concentrations of the drug (ie, negative biotics. For patients for whom an alternate antibiotic cannot skin test reactivity in a panel of normal, nonexposed volun- be used, successful rapid induction of drug tolerance for teers) may provide useful information. Table 18 lists nonir- IgE-mediated hypersensitivity to vancomycin has been ritating concentrations for intradermal skin testing for 15 described.345,348,466,467 commonly used antibiotics. If the skin test result is positive Although aminoglycosides rarely cause hypersensitivity under these circumstances, it is likely that drug specific IgE reactions, there are individual case reports of IgE-mediated antibodies are present. Therefore, the patient should receive systemic reactions.468-470 Rapid induction of drug tolerance an alternative non–cross-reacting antibiotic or undergo rapid may be indicated when the allergy is thought to involve IgE induction of drug tolerance. On the other hand, a negative antibodies and no alternative antibiotic is available.468 Both skin test result does not denote that drug specific IgE anti- graded challenge and induction of drug tolerance procedures bodies are absent because it is possible that a drug metabolite should be performed by specialists experienced with these not present in the test reagent may be the relevant allergen. protocols and the possible adverse events associated with However, if this particular antibiotic is required for treatment, them. The degree of allergic cross-reactivity among amino- the amount of drug injected intracutaneously can be used as glycosides is unknown but is assumed to be high. the initial starting dose for rapid induction of drug tolerance. Quinolones are a class of antibiotics related to nalidixic In skin test–negative patients who have mild reaction histo- acid. Anaphylactoid reactions to this class of drug after the

273.e51 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY initial dose have been reported to occur at a rate of 1:1,000 than 1% of patients.40-43 However, life-threatening allergic and 1:100,000.471-473 Reports of IgE-mediated anaphylactic reactions to human insulin and insulin analogs (Aspart, reactions to quinolones appear to be increasing, possibly Lispro, and Glargine) have been documented and can be because of increased use of these agents.28-31 In vitro studies confirmed by appropriate intracutaneous and/or in vitro test- suggest a large extent of allergic cross-reactivity among quin- ing.44,45 The latter tests have also revealed immunologic olones,2,28,29 but there are no clinical studies to confirm this. cross-reactivity to porcine and bovine insulin.488 Tolerance to Delayed cutaneous eruptions appear in approximately 2% of insulin may be achieved by continuous subcutaneous infusion quinolone-treated patients.32,33 There is evidence to show that of insulin lispro.489,490 Adverse reactions to inhaled insulin drug-specific T cells are responsible for delayed maculopap- have not been reported, but there is a marginally greater ular exanthems from quinolones.472 decline in pulmonary function tests in subjects with asthma or Although bacitracin is a common cause of type IV contact chronic obstructive pulmonary disease.491 As has been the dermatitis reactions,474 there are rare published reports of case for many years, protamine (ie, neutral Hagedorn insulin) IgE-mediated anaphylactic reactions to bacitracin.475-477 may either masquerade as insulin allergy or act as a concur- rent sensitizing drug.40,492 C. Antimycobacterial Drugs Leukocytoclastic vasculitis, generalized arteritis, granulo- Summary Statement 120: Allergic drug reactions to anti- matous hepatitis, and autoimmune pemphigus vulgaris are mycobacterial drugs present significant problems in the im- rare immune-mediated reactions that have been described to plementation of long-term treatment regimens and preventing occur during treatment with metformin and/or sulfonylurea drug resistance to Mycobacterium tuberculosis. (C) antidiabetic agents.47-53 Shortly after the introduction of the first-line drugs (strep- tomycin and para-amino ) as effective therapy E. Cancer Chemotherapeutic Agents for tuberculosis, it became apparent that these drugs can Summary Statement 123: Cancer chemotherapeutic agents, induce both minor and life-threatening allergic reactions.478-480 such as taxanes (paclitaxel, docetaxel), platinum compounds The frequency of allergic reactions to is still (cisplatin, carboplatin, oxaliplatin), and asparaginase, may considerable when used alone or in combination with other cause severe immediate-type reactions, which may be either agents.481,482 Many allergic reactions were also encountered anaphylactic or anaphylactoid in nature. (C) after use of second-generation drugs, including isoniazid, Summary Statement 124: For some chemotherapeutics ethambutol, pyrazinamide, and .34 These include (primarily the platinum-based compounds), skin testing may anaphylaxis, angioedema, pulmonary infiltrates, and cutane- assist in identifying allergic patients who are at increased risk ous reactions.35-39 Many cases of rifampicin-induced, non-IgE for an allergic reaction and for confirming IgE-mediated immune reactions present with a flulike syndrome with sub- sensitivity. (C) sequent thrombocytopenia, hemolytic anemia, and renal fail- Summary Statement 125: Rapid induction of drug tolerance ure.483 A significant confounder is the fact that a relatively protocols are available for most chemotherapeutic agents that high occurrence (up to 1%) of toxic rather than allergic cause immediate-type reactions, but they are not uniformly hepatitis may occur in the therapeutic course of isoniazid or successful. (C) rifampicin.34 Occasionally, patients may develop hypersensi- Summary Statement 126: Methotrexate can cause intersti- tivity to multiple antimycobacterial drugs (eg, streptomycin, tial reactions in the lungs, which can progress to fibrosis if rifampicin, and ethambutol) either concurrent or sequential.34,481 use of the drug is continued. (C) In addition to the previously discussed multisystem syn- Hypersensitivity reactions have been reported for virtually drome, dapsone, the drug of choice in the treatment of all commonly used chemotherapeutic agents. Reactions range and neutrophilic dermatoses, may rarely induce from mild cutaneous eruptions to fatal anaphylaxis. In some other immune-mediated reactions, such as rash DRESS, cases, it is difficult to determine whether a reaction is ana- renal hypersensitivity vasculitis, angioedema, and/or inter- phylactic (ie, mediated by drug specific IgE antibodies) or stitial pneumonitis.484-487 anaphylactoid (due to nonimmune of mast cells and basophils). Some reactions may be the result of excipi- D. Diabetes Medications ents rather than the active drug, such as Cremophor-EL, a Summary Statement 121: The advent of human recombi- lipid solvent vehicle used in paclitaxel and other intravenous nant insulin has greatly reduced the incidence of life-threat- chemotherapeutics. Cremophor-EL is a nonionic emulsifier ening allergic reactions to approximately 1%. (C) consisting of a mixture of amphophilic molecules that form Summary Statement 122: Metformin and sulfonylurea micelles, spherical “core-shell” structures. These Cremo- antidiabetic drugs rarely cause immune-mediated reactions, phor-EL particles in blood activate complement, leading to such as leukocytoclastic vasculitis, generalized arteritis, gran- production of anaphylatoxins.493 ulomatous hepatitis, and autoimmune pemphigus vulgaris. In addition to life-threatening reactions, cancer chemother- (C) apeutic agents (eg, cyclophosphamide, methotrexate) may Since the introduction of purified human recombinant in- induce a variety of cutaneous IgE and non-IgE allergic man- sulin, allergy to insulin is rare and is now encountered in less ifestations. These include urticaria, erythroderma, mixed cu-

VOLUME 105, OCTOBER, 2010 273.e52 taneous dermatitides, leukocytoclastic vasculitis, and toxic Summary Statement 128: The most common adverse drug epidermal necrolysis. The possibility of such reactions is reaction in HIV-positive patients who take trimethoprim- particularly important when toxic drugs are used to treat sulfamethoxazole is a morbilliform and/or maculopapular immunologically mediated conditions such as vasculitis. eruption, often associated with fever that occurs after 7 to 12 In the taxane family, paclitaxel and docetaxel produce days of therapy. (C) anaphylactoid reactions in as many as 42% of patients on first Summary Statement 129: HIV-positive patients who have administration,54 suggesting an anaphylactoid mechanism. experienced typical delayed exanthematous reactions to tri- Pretreatment with systemic corticosteroids and antihistamines methoprim-sulfamethoxazole and who require treatment with prevents the reaction in more than 90% of patients.55 Patients the drug (such as for Pneumocystis jiroveci pneumonia) may who react despite pretreatment can usually be successfully undergo one of several published trimethoprim-sulfamethox- desensitized.56,57 Another option for patients who react to azole induction of drug tolerance protocols. (D) Usually, this paclitaxel is to switch to docetaxel because most are able to should be done after waiting for at least 1 month after the tolerate it.59 reaction to increase the likelihood of success. (D) Platinum compounds (cisplatin, carboplatin, and oxalipla- Summary Statement 130: Reintroduction of trimethoprim- tin) typically cause hypersensitivity reactions after comple- sulfamethoxazole in HIV-positive patients with a history of tion of several treatment courses,60,61 suggesting an immuno- more severe reactions to trimethoprim-sulfamethoxazole, logic mechanism. Pretreatment with corticosteroids and such as Stevens-Johnson syndrome or toxic epidermal antihistamines does not prevent these reactions.62 Skin testing necrolysis, is generally contraindicated, with rare exceptions, with the undiluted drug has been found to identify patients at such as treatment of a life-threatening infection in which case risk of reactions, and skin testing should be repeated before the benefit of treatment outweighs the risk of a potentially each subsequent course with the drug.61,63,64 For patients with life-threatening reaction. (D) positive skin test results, various rapid induction of drug Summary Statement 131: Antiretroviral drugs used for tolerance protocols have been reported, but they are not highly active antiretroviral therapy (HAART) of HIV-in- uniformly successful.61,63,64 Immediate-type reactions to as- fected patients may cause allergic reactions of various kinds. paraginase occur in as many as 43% of patients, and the (C) reaction rate increases after the fourth weekly dose.494 It is Summary Statement 132: Abacavir is the most common unknown whether the mechanism is anaphylactic or anaphy- HAART drug to cause severe allergic reactions, and this risk lactoid, and it may be different in different patients. Although is associated with the presence of HLA B 5701. (C) use of skin testing with asparaginase before treatment has Drug reactions are common in patients infected with HIV, been recommended, it has not been shown to identify all and in some cases the incidence of reactions may be related patients at risk of reactions. Rapid induction of drug tolerance to the degree of immunodeficiency.69-73 These reactions cause with asparaginase has been described.350 In patients who react significant morbidity and mortality in this population. The to asparaginase, substitution of either pathogenesis of adverse drug reactions in HIV-positive pa- Erwinia asparaginase or pegylated asparaginase may allow tients is unknown, but it is likely that the responsible mech- 70 them to complete the treatment course.495,496 anism is multifactorial. Although these reactions are com- Methotrexate is a cause of noncytotoxic pulmonary reac- monly referred to as being “allergic,” it is likely that both tions.65,66 Methotrexate pneumonitis occurs most frequently toxic and immunologic mechanisms are involved. There are within the first year of treatment, and the reported incidence data to support several risk factors for the development of of this reaction varies from 0.86% to 6.9%.67,68 Symptoms of adverse drug reactions in HIV-positive patients. These in- fever, cough, and dyspnea may occur anywhere from several clude coexistent or Epstein-Barr virus infec- days to several months after initiation of therapy. The chest tions, altered , slow acetylator phenotype, radiograph is characterized by a diffuse, fine interstitial in- relative deficiency of or other scavengers, in- filtrate. When use of the drug is discontinued, symptoms and creased expression of major histocompatibility complex class I and II on keratinocytes, and high-dose trimethoprim-sulfa- pulmonary infiltrates typically clear within a few days. If the 298,498-504 drug is inadvertently continued, interstitial fibrosis may en- methoxazole treatment. sue. Bleomycin and procarbazine are most commonly asso- Adverse reactions to sulfonamides may complicate both ciated with cytotoxic pulmonary reactions but also have been treatment and prophylaxis of Pneumocystis jiroveci pneumo- nia in many patients with AIDS. However, unlike reactions to reported to cause reactions similar to those ascribed to metho- 505 506 trexate.66,240 Hypersensitivity pneumonitis in association with amoxicillin and antimycobacterial agents, adverse reac- the use of an alkylating agent has also been documented.497 tions to sulfonamides may decrease with HIV disease pro- gression.72 Adverse cutaneous sulfonamide reactions may be F. HIV Medications tolerated without ceasing therapy in some cases. The use of Summary Statement 127: Patients infected with HIV have sulfonamides should be discontinued immediately, however, an increased frequency of adverse reactions to a variety of if any of the following develop: (1) persistent rash and/or drugs, and the pathogenesis of these reactions is likely mul- fever for more than 5 days, (2) absolute count less tifactorial. (C) than 500/␮L, (3) hypotension, (4) dyspnea, or (5) any signs of

273.e53 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY blistering, of the skin, or mucous membrane tolerance vs rechallenge (single dose), the success rates were involvement. 79% and 72%, respectively, and the difference was not sta- There appears to be a relationship between the develop- tistically significant.83 Sulfadiazine, acyclovir, zidovudine, ment of adverse sulfonamide reactions and the dose admin- dapsone, and pentamidine induction of drug tolerance proto- istered because some patients can continue treatment after cols have also been developed for patients with AIDS.86-91 interruption of therapy or lowering of the dosage.499 The In addition to trimethoprim-sulfamethoxazole, patients degree of clinical cross-sensitivity among different sulfon- with AIDS may have an increased frequency of various drug amides is not known. The degree of clinical cross-sensitivity allergic reactions and syndromes to a number of other agents, between trimethoprim-sulfamethoxazole and dapsone is including antituberculous agents, pentamidine, amoxicillin- thought to be low, and it appears that most patients who react , clindamycin, carbamazepine, phenytoin, tha- to trimethoprim-sulfamethoxazole tolerate dapsone.507 Dap- lidomide, , and .505,506,511-514 The fact sone, however, probably should not be used in those patients that these reactions are clinically diverse suggests that they in whom trimethoprim-sulfamethoxazole caused severe reac- are likely produced by a variety of mechanisms. tions, such as SJS, or visceral involvement, such as hepatitis Twenty antiretroviral drugs are approved by the US Food or pneumonitis. and Drug Administration for HAART of HIV-infected pa- The most common reaction to sulfonamides is a morbilli- tients.92,93 Many of these drugs have been associated with form, maculopapular eruption often associated with fever that hypersensitivity responses ranging from mild cutaneous occurs after 7 to 12 days of therapy. Immediate (anaphylaxis, rashes to life-threatening SJS and TEN.94 The most common urticaria/angioedema) and delayed (erythema multiforme mi- HAART offenders are abacavir, all nonnucleoside reverse nor, erythema multiforme major/SJS, TEN) hepatic, hemato- transcriptase inhibitors, and amprenavir.93 Abacavir, a nucle- logic, renal, and immune complex reactions may occur. The oside analogue reverse transcriptase inhibitor, causes severe spectrum of clinical manifestations of sulfonamide reactions hypersensitivity in 4% to 5% of patients.95,96 Such reactions in patients with AIDS suggests that most of these reactions have been identified with a genetic risk factor, the presence of are not IgE mediated. In addition, the observation that induc- HLA B 5701.97,98 Among the nonnucleoside reverse trans- tion of drug tolerance protocols beginning with relatively criptase inhibitors, nevirapine has been cited most often as a high starting doses are often successful lends further support cause of rash or combination of symptoms of fever, rash, and to the impression that an alternative pathogenic mechanism is hepatitis.515 This drug has been associated with an interaction operative. Sulfonamide specific IgG and IgM antibodies have between HLA-DRB1*0101 and CD4ϩ T cells higher than 250 been found in patients with AIDS, both those with and cells/␮L.516 Women are at increased risk for nevirapine and without skin reactions to sulfonamides.508,509 It is unlikely that other HAART-induced drug reactions.515 these antibodies play a pathogenic role in sulfonamide hy- Coadministration of tuberculosis drugs and antiretroviral persensitivity reactions. For HIV-positive individuals who therapy in AIDS patients infected with Mycoplasma hominis develop typical delayed maculopapular rashes after tri- and atypical organisms (Mycobacterium avium, Mycobacte- methoprim-sulfamethoxazole administration, many different rium intracellulare) is often required. This combination is induction of drug tolerance protocols have been developed associated with 3 major complications: (1) induction of cy- 74-85 and used successfully. Reintroduction of trimethoprim- tochrome P450 enzymes by rifampicin induces reduction of sulfamethoxazole by 1 of these protocols optimally should antiretroviral drug levels, (2) overlapping toxic effects and not take place any earlier than 1 month after the initial occur often, and (3) an immunologic reac- adverse reaction, and none of these protocols should be used tion termed “the immune reconstitution inflammatory syn- in individuals with a history of bullous dermatitis or SJS. drome” may develop.517 It is postulated that increased risk of However, it may be started earlier if treatment of a serious 518 anaphylaxis is due to a skewing of TH2 cytokine cytokines. infection requiring these drugs is necessary. Although rein- Severe cutaneous hypersensitivity reactions, anaphylaxis, ful- troduction of trimethoprim-sulfamethoxazole in HIV-positive minant hepatitis, and SJS have been reported.37,519,520 patients with a history of more severe reactions to tri- methoprim-sulfamethoxazole, such as SJS is generally con- G. Disease-Modifying Antirheumatic Drugs (DMARDs) traindicated, successful trimethoprim-sulfamethoxazole de- Summary Statement 133: Apart from adverse reactions to sensitization has been described in 2 patients with a history of aspirin, other NSAIDs, and certain pyrazolone derivatives SJS.510 This should be considered only if alternate therapy has (discussed in VII-R), a variety of allergic reactions to other failed and the patient has a life-threatening infection, in DMARDs may occur. (C) which case benefit of treatment with trimethoprim-sulfame- Parenteral gold salts were responsible for isolated instances thoxazole outweighs the risk of a potentially life-threatening of anaphylaxis, hypersensitivity pneumonitis, and severe mu- reaction. cocutaneous reactions.521-524 D-penicillamine has been noted It is not clear how or to what extent the immune response to induce bullous dermatoses and autoimmune diseases.525 to trimethoprim-sulfamethoxazole is modified during these The potentially serious immunotoxic effects of methotrexate types of induction of drug tolerance procedures. In a random- have been previously discussed. with ized trial of trimethoprim-sulfamethoxazole induction of drug azathioprine may lead to leukocytoclastic vasculitis in ap-

VOLUME 105, OCTOBER, 2010 273.e54 proximately 10% of such treatments.526 Hydroxychloroquine I. Modifying Drugs for Dermatologic Diseases is rarely associated with phototoxic and photoallergic derma- Summary Statement 135: Allergic reactions to immunosup- titis.527 Sulfasalazine-induced reactions include DRESS and pressant and anti-inflammatory drugs are commonly encoun- extrinsic allergic alveolitis.237,528 Allergic reactions also occur tered in the treatment of chronic cutaneous diseases. (C) after use of the newest DMARD, . These include The modern dermatologic armamentarium consists of a erythema multiforme, lupus erythematosus, and TEN.529-531 spectrum of T-cell immunosuppressant drugs, such as mac- Infusion reactions, frank allergic reactions, and new autoan- rolides (cyclosporine, tacrolimus, pimecrolimus, sirolimus), tibodies have been observed after treatment by , an dapsone, mycophenolate mofetil, and previously discussed interleukin 1 .532,533 monoclonal antibodies. The macrolide immunosuppressants, which are extensively used to prevent transplantation rejec- H. Immunomodulatory Agents for Autoimmune Diseases tion and to treat inflammatory bowel disease, are also used to Summary Statement 134: Although hypersensitivity reac- treat psoriasis, a TH1-cytokine-mediated disease. In general, tions to several unique therapeutic agents for autoimmune immune-mediated reactions to these agents are rare. Infusion diseases have already occurred, it is too early to assess the reactions to cyclosporine have been attributed to an IgE- global impact of adverse events for diverse immunologic mediated reaction to the Cremophor-EL solvent. Although interventions in early development. (C) ingestion of cyclosporine is often tolerated after such severe Glatiramer acetate (Copaxone) was developed as a copol- events, anaphylactic shock has also rarely occurred after oral ymer with a mixture of amino acids resembling those of cyclosporine.547-550 Angioedema and leukocytoclastic vascu- myelin basic protein to diminish the rate of relapse in mul- litis have been reported after use of tacrolimus and sirolimus, 551-554 tiple sclerosis.534 Hypersensitivity reactions in the form of respectively. Both cyclosporine and tacrolimus may be 555,556 injection site and erythema nodosum have occurred535,536; associated with elevated total IgE levels. In the case of instances of systemic reactions and anaphylaxis have been tacrolimus, food and inhalant specific IgE levels were also reported.537,538 On the basis of a similar rationale, altered elevated, and several children developed clinical food aller- ligands were evaluated in several phase 2 trials.539 gies, suggesting that these agents may induce a shift to a TH2 pattern.552,554,556 Apart from its toxic effects of methemo- Although the efficacy results were promising, anaphylactic globulinemia, hemolytic anemia, and previously discussed reactions to the self-peptide were encountered. Skin reactions 540 hypersensitivity effects, dapsone may induce a potentially are common after the use of interferon beta-1b. fatal multisystem disorder known as the dapsone hypersen- The immunologic complexity of systemic lupus ery- sitivity syndrome.557,558 Urticaria and a severe papulosqua- thematosus provides multiple therapeutic targets and cor- mous skin eruption have been reported after use of CellCept responding therapies: B cells (rituximab), T- and B-cell (mycophenolate mofetil).559,560 Of particular interest to aller- collaboration (CTLA4Ig), B-cell factors (anti-BLyS, anti- gists is the fact that all of these drugs have been and are being BAFF), complement (anti-C5a antibodies), and suppressor used for the treatment of refractory atopic dermatitis or proteins (suppressor of cytokine signaling-1).541 Thus far, chronic idiopathic urticaria.561-564 only rituximab has received significant clinical experience, and reactions to this agent will be discussed in section J. Perioperative Agents VII. T.186 However, as some of the other biologic modifiers Summary Statement 136: Anaphylactic or anaphylactoid become part of the clinical armamentarium within the next reactions during the operative and perioperative periods may few years, the possibility of allergic reactions to other new be caused by induction agents, muscle-relaxing agents, opi- ates, antibiotics, and latex allergy. (C) agents may be anticipated. Anaphylactic or anaphylactoid reactions are not infrequent Immunomodulation strategies are being actively pursued during general .565 The incidence of these reactions for prevention or attenuation of . Thus far, during general anesthesia is estimated to be between 1 in most of these interventions are not autoantigen/HLA specific. 2,100 to 1 in 20,000 anesthesias.565,566 The higher incidence (1 Among the most promising of these immunotolerance inter- ␤ per 2,100 operations) was reported in a 12-year French pe- ventions are (1) -chain of insulin in incomplete Freund diatric survey.566 The reactions may be due to induction adjuvant, (2) an altered insulin peptide, (3) an alum-formu- agents, neuromuscular blocking agents, antibiotics, opiates, lated glucose acid decarboxylase , (4) rituximab, (5) and latex. Because anaphylactic reactions cannot be distin- CTLA-4 immunoglobulin, (6) anti-CD40L monoclonal anti- guished from anaphylactoid, nonimmune occurrences, it has body, and (7) anti-CD3 (anti–T-cell) monoclonal antibod- been recommended that plasma histamine, tryptase, and spe- ies.542-544 It is uncertain whether use of adjuvants (incomplete cific IgEs (if available) may be ordered at the time of reaction Freund adjuvant or alum) will counteract IgE-mediated reac- and skin tests be performed later.99 The incidence of life- tions. As previously discussed, human monoclonal antibodies threatening reactions to muscle relaxants has been estimated differ with respect to allergic effects, so it is not yet known at 1 in 4,500 anesthesia events.567 Some muscle relaxants, how widespread use of anti-CD3 will fare in this respect, but such as curare, are potent histamine-releasing agents.568,569 a recent showed promise.545,546 Others, such as atracurium, pancuronium, and vecuronium,

273.e55 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY are less potent in this regard. Drug specific IgE antibodies opiates are difficult to interpret because these agents cause have been demonstrated to some of these agents so that it is release of histamine from skin mast cells in all patients. apparent that reactions to muscle relaxants may involve more Dilute skin test concentrations have been recommended if an than 1 mechanism.570 Life-threatening reactions to , IgE-mediated reaction is suspected.580 A single case of a which is formulated with oil, egg phosphatide, and documented IgE-mediated reaction to has been sometimes metabisulfite, have been reported.571-573 Hyaluron- reported.581 Some reactions can be attenuated by pread- idase in ophthalmic anesthesia may cause angioedema.574 The ministration of antihistamines. Narcotic-induced pseudoaller- diagnosis and management of reactions occurring during gic reactions are rarely life-threatening. If there is a history of and after are discussed in more detail in the Anaphy- such a reaction to an opiate and analgesia is required, a laxis Practice Parameter326 and Diagnostic Testing Practice nonnarcotic alternative pain medication should be selected. If Parameter.330 this does not control pain, graded challenge with an alterna- tive opiate up to a dose that will control pain should be tried. K. Blood and Blood Products Summary Statement 137: Reactions due to blood and blood M. Corticosteroids products include urticaria, anaphylaxis (particularly in pa- Summary Statement 139: Immediate-type reactions to cor- tients with complete IgA deficiency), anaphylactoid reac- ticosteroids are rare and may be either anaphylactic or ana- tions, and transfusion-related acute lung injury (TRALI). (C) phylactoid in nature. (C) Acute urticarial reactions occur in 1% to 3% of blood Summary Statement 140: Most reported reactions to corti- transfusions, whereas significant /laryn- costeroids involved intravenous methylprednisolone and hy- geal edema and anaphylactic shock occur in 0.1% to 0.2% drocortisone, and preservatives and diluents have also been and 0.002% to 0.005%, respectively.575 Diagnostic in vivo or implicated. (C) in vitro tests are not available for such reactions. Rarely, a Allergic contact dermatitis (Gell-Coombs type IV reaction) patient totally lacking serum IgA may develop specific IgE or due to topical application of corticosteroids is the most com- IgG antibodies against IgA and subsequently react to IgA in mon type of allergic reaction induced by this class of drugs. the or in trace amounts contained in some Rarely, immediate-type allergic reactions to corticosteroids preparations of intravenous gamma globulin.576,577 Activation have been described. Most such reported reactions are due to of complement and other non–IgE-mediated reactions may intravenous administration of methylprednisolone and hydro- also occur after blood transfusions, presumably as a result of cortisone.53,106-111 Patients with AERD or renal transplants alloantigenic reactivity.575 Reactions to human serum albu- may be at increased risk of reacting to corticosteroids, but this min are extremely rare (0.01%), but occasionally allergic could be due to increased use of corticosteroids in these patients exhibit positive prick test results to albumin-contain- patients. In most cases, drug specific IgE has not been de- ing diluent solutions.578 Such reactivity has been demon- tected (either via skin testing or in vitro tests). Hence, it is strated in mite–sensitive patients tested with mite unclear whether these reactions are anaphylactoid or repre- culture medium containing human serum albumin compo- sent true IgE-mediated allergy. Some of the reactions are nents. TRALI is a complex syndrome that has multiorgan believed to be secondary to the diluent or , rather manifestations and has only recently been identified to be an than the active drug.107,296 Although corticosteroid-induced important cause of transfusion-associated morbidity and mor- reactions are rare, the possibility should be entertained in tality.104,105 The pathogenesis of TRALI is as yet unknown, patients who experience immediate symptoms (urticaria, an- but it is postulated to involve (1) an antibody-mediated event gioedema, bronchospasm) in the context of receiving the caused by transfusion of donor antibodies (anti-HLA or an- drug, with no other ascertained cause. Evaluation should tigranulocytic) into patients whose leukocytes express the include skin testing with the corticosteroid in question, al- cognate antigen and/or (2) pulmonary endothelial activation though its predictive value is uncertain. Skin testing with the leading to endothelial damage and capillary leak syndrome diluent itself may also be helpful. Because most (but not all) after the transfusion.579 patients appear to be able to tolerate other corticosteroids, management should focus on finding an alternate agent for L. Opiates future use. If a patient with suspected allergy to a corticoste- Summary Statement 138: Opiates and their analogs are a roid requires treatment with it, rapid induction of drug toler- common cause of pseudoallergic reactions that are generally ance should be performed. mild, are not life-threatening, and can be attenuated by pread- ministration of histamine1 receptor antihistamines. (C) N. Protamine Opiates such as morphine, meperidine, , and nar- Summary Statement 141: Severe immediate reactions may cotic analogs can stimulate mast cell–mediated release di- occur in patients receiving protamine for reversal of hepa- rectly without a specific immunologic mechanism. Patients rinization. (C) who exhibit this tendency may experience generalized pruri- Summary Statement 142: Diabetic patients receiving pro- tus and urticaria after administration of a narcotic . tamine-containing insulin are at greatest risk of severe reac- Occasional mild wheezing may be noted. Skin test results to tions due to intravenous protamine. (C)

VOLUME 105, OCTOBER, 2010 273.e56 is a low-molecular-weight (4500 Da) pathway with generation of bradykinin, a potent vasoactive polycationic protein isolated from salmon testes. Its original mediator, and generation of C3a and C5a anaphylatoxins.113 use was to complex insulin (neutral protamine Hagedorn Clinically, reactions to contaminated heparin products were [NPH] insulin) to delay absorption, but it is also used to associated with hypotension and abdominal pain, and vari- reverse the effects of heparin after a variety of ably angioedema, but typically lacked urticaria and pruri- procedures, including cardiopulmonary bypass and hemodi- tus.114 The findings of abdominal pain and angioedema are alysis. Immediate generalized reactions to protamine, includ- somewhat analogous to C1 inhibitor deficiency in which ing hypotension, shock, and death, have been reported.100,101 symptoms are due to local production of bradykinin. The occurrence of dose-dependent hypotension after rapid P. Local Anesthetics intravenous administration may be a manifestation of non- Summary Statement 144: Most adverse reactions to local specific histamine release.582 However, the fact that diabetic anesthetics are not due to IgE-mediated mechanisms but are patients receiving protamine-containing insulins appear to be due to nonallergic factors that include vasovagal responses, at 40 to 50 times greater risk for developing anaphylaxis and anxiety, toxic reactions including dysrhythmias, and toxic or other adverse reactions to intravenous protamine suggests idiosyncratic reactions due to inadvertent intravenous epi- that immune mechanisms are also involved.102,103 IgE and IgG nephrine effects. (C) antibodies directed against protamine have been detected in Summary Statement 145: To exclude the rare possibility of some patients who reacted to protamine.100 IgE-mediated an IgE-mediated reaction to local anesthetics, skin testing and reactions to the protamine moiety of NPH insulin also have graded challenge can be performed in patients who present been reported.583 There are no widely available alternate with a reaction history suggestive of possible IgE-mediated agents for heparin reversal. Pretreatment with corticosteroids allergy to these drugs. (B) and antihistamines has been recommended, but no studies Possible systemic allergy to local anesthetics is often of have shown this to be efficacious. concern to patients and their dentists or physicians. Docu- O. Heparin mentation of IgE-mediated reactions is extremely rare.115-118 Summary Statement 143: Hypersensitivity reactions to un- Most adverse reactions to local anesthetics are due to nonal- fractionated heparin and low-molecular-weight heparin are lergic factors that include vasovagal responses, toxic or idio- uncommon and include thrombocytopenia, various cutaneous syncratic reactions due to inadvertent intravenous epineph- eruptions, hypereosinophilia, and anaphylaxis. (C) rine, or anxiety.589-592 Of these, anxiety is probably the most Hypersensitivity reactions to unfractionated heparin and difficult to manage. Therefore, the history of a previous low-molecular-weight heparin are uncommon and include reaction must be carefully evaluated. It is necessary to deter- thrombocytopenia, various cutaneous eruptions, hypereosino- mine the type of local anesthetics to be used. Local anesthet- philia, and anaphylaxis. Mild thrombocytopenia is due to ics are either group 1 benzoic acid esters (eg, , platelet aggregation and occurs in 1% to 3% of patients benzocaine) or group 2 amides (eg, , mepivacaine). treated with unfractionated heparin. Severe thrombocytope- On the basis of patch testing, the benzoic acid esters cross- nia is caused by immune complexes, a component of which is react with each other, but they do not cross-react with the heparin-dependent IgG specific for platelet factor 4.112 This group 2 amide drugs. It is not known what, if any, relevance reaction usually occurs after approximately 5 days of treat- this has on immediate-type reactions to local anesthetics. ment with unfractionated heparin and is associated with de- Graded challenge tests may then be performed using incre- velopment of thrombosis and necrosis. Low-molecular- mental concentrations of the that the dentist weight heparin does not cause anti–platelet 4 IgG-related intends to use. This test reagent should not contain epineph- reactions, but it may cause thrombocytopenia. Although im- rine or other additives, such as parabens or sulfites. When mediate hypersensitivity reactions to unfractionated heparin there is concern about a previously reported reaction, skin and low-molecular-weight heparin are rare, anaphylactic and testing and incremental challenge with a local anesthetic is a anaphylactoid reactions have been documented.584,585 The ex- reasonable approach in the evaluation of a possible reaction. tent of allergic cross-reactivity between high- and low-mo- Although there are slight differences in reported graded chal- lecular-weight is unknown.586,587 Management of lenge procedures, a typical protocol is as follows. Skin prick patients with allergic reactions to heparin may require switch- tests are first performed with the undiluted anesthetic. If the ing to a direct inhibitor such as a hepanoid (danap- result is negative, successive injections (subcutaneous or in- aroid) or a ( or argatroban). However, pa- tracutaneous) of 0.1 mL of 1:100 dilution, 1:10 dilution, and tients may develop antihirudin antibodies, and a small the full-strength solution are given at 15-minute intervals. If percentage of such patients may experience anaphylaxis.588 A reactions are not encountered, 0.5 to 1 mL of the anesthetic is recent outbreak of anaphylactic reactions to heparin in the injected subcutaneously. A step may be added after United States and Germany was attributed to a contaminant in the skin prick test and before challenging with the local heparin lots, an oversulfated form of chondroitin sulfate. This anesthetic. With this protocol, there have been no serious oversulfated chondroitin sulfate contaminant has been shown allergic reactions reported after administration of local anes- in vitro and in vivo to cause activation of the kinin-kallikrein thetics if the skin test results and test dosing are negative.591

273.e57 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY A more recent evaluation of a similar protocol revealed no mild, self-limited cutaneous eruptions that appear to be T-cell incidence of an allergic reaction in a total of 256 referred mediated, although more serious reactions, such as SJS, TEN, patients.593 Test reagents in this investigation included pre- and DRESS syndrome, have been described. servatives and epinephrine. The investigators concluded that Adverse reactions to RCM are classified as chemotoxic or local anesthetic tests could be performed with formulations anaphylactoid. Chemotoxic reactions (cardiotoxicity, neuro- that contain either preservatives and/or epinephrine. toxicity, and ) are related to the chemical prop- Dentists and other health care professionals may develop erties of the contrast agent, and they are dose and concentra- contact dermatitis from local anesthetics. In the event that this tion dependent. Chemotoxic reactions tend to occur in occurs, patch testing should be performed to determine the medically unstable patients who are debilitated. Anaphylac- degree of sensitization to the suspected local anesthetic and toid reactions occur in approximately 1% to 3% of patients identify the agent(s) that is least likely to produce a reaction. who receive ionic RCM and less than 0.5% of patients who False-positive intracutaneous test results may occur in receive nonionic agents.119,120 Severe life-threatening reac- some history-negative patients and patients with a history of tions are less common, occurring in 0.22% of patients receiv- adverse reactions to local anesthetics.594 On the basis of the ing ionic RCM and 0.04% of patients receiving nonionic low pretest probability of IgE-mediated local anesthetic al- agents.121 The fatality rate from RCM is approximately 1 to 2 lergy and the occurrence of false-positive results, it is unclear per 100,000 procedures, and it is similar for both ionic and whether intracutaneous tests have any benefit in the diagnos- nonionic agents.596,597 Risk factors for anaphylactoid reactions tic approach to local anesthetic allergy.593 Rare patients may to RCM include female sex, asthma, and a history of previous also have positive skin test results to methylparabens in the anaphylactoid reaction to RCM; ␤-blocker exposure and/or local anesthetics, and some of these may be false-positive presence of cardiovascular conditions is associated with skin test results because subsequent results of subcutaneous greater risk for more serious anaphylactoid reaction.122-126 challenges to local anesthetic with methylparabens are neg- A relationship between anaphylactoid reaction to RCM and ative.595 Subcutaneous local anesthetic challenges using a “seafood allergy” is a frequent misconception. There is no graded incremental approach after skin tests have been re- convincing evidence in the medical literature that individuals ported to be a safe method in a study of 236 patients with with “seafood allergy” are at elevated risk for anaphylactoid histories of adverse reactions to local anesthetics.593 Alterna- reaction to RCM compared with the general population. The tively, a more rapid subcutaneous challenge approach using pathogenesis of anaphylactoid reactions is also unrelated to 1.0 mL of (placebo) followed in 20 minutes by 1.0 mL iodine. Rates of anaphylactoid reactions to low-osmolar con- of undiluted local anesthetic was a safe and effective method trast agents are significantly lower than rates observed with 595 in a study of 252 patients. conventional contrast media,121 yet their content of iodine is Q. Radiocontrast Media (RCM) similar. RCM reactions are typically not mediated by specific Summary Statement 146: Anaphylactoid reactions occur in IgE antibodies with rare exceptions.598 RCM likely has direct approximately 1% to 3% of patients who receive ionic RCM effects on mast cells and basophils, leading to degranulation and less than 0.5% of patients who receive nonionic RCM. and systemic mediator release, which accounts for the clinical (C) manifestations of anaphylactoid reactions. Complement acti- Summary Statement 147: Risk factors for anaphylactoid vation may account for some reactions. reactions to RCM include female sex, atopy, concomitant use Management of a patient who requires RCM and has had of ␤-blocking drugs, and a history of previous reactions to a prior anaphylactoid reaction to RCM includes the follow- RCM. (C) ing: (1) determine whether the study is essential; (2) deter- Summary Statement 148: Although asthma is associated mine that the patient understands the risks; (3) ensure proper with an increased risk of a RCM reaction, specific sensitivity hydration; (4) use a nonionic, iso-osmolar RCM, especially to seafood (which is mediated by IgE directed to proteins) in high-risk patients (asthmatic patients, patients taking does not further increase this risk. There is no evidence that ␤-blockers, and those with cardiovascular disease), and (5) sensitivity to iodine predisposes patients to RCM reactions. use a pretreatment regimen that has been documented to be (C) successful in preventing most reactions.127-130 One reported Summary Statement 149: Patients who experienced previ- regimen consists of , 50 mg, at 13, 7, and 1 hour ous anaphylactoid reactions to RCM should receive nonionic, before the procedure; , 50 mg, at 1 hour iso-osmolar agents and be treated with a premedication reg- before the procedure; and either , 25 mg, or albu- imen, including systemic corticosteroids and histamine1 re- terol, 4 mg, at 1 hour before the procedure. However, the ceptor antihistamines; this will significantly reduce, but not latter agents may not be favorable from a risk-benefit stand- eliminate, risk for anaphylactoid reaction with reexposure to point in patients with cardiovascular disease. Although his- contrast material. (D) tamine2 receptor antagonists are beneficial in the treatment of 326 Summary Statement 150: Delayed reactions to RCM, de- anaphylaxis, when the addition of histamine2 receptor an- fined as reactions occurring 1 hour to 1 week after adminis- tagonists 1 hour before RCM procedures was studied, para- tration, occur in approximately 2% patients. (C) Most are doxically, a modest increase in reaction rate was observed.127

VOLUME 105, OCTOBER, 2010 273.e58 Delayed reactions to RCM, defined as those occurring Aspirin and NSAIDs can cause a spectrum of drug allergic between 1 hour and 1 week after administration, occur in reactions, including exacerbation of underlying respiratory approximately 2% of patients.131 These reactions most com- disease, urticaria, angioedema, anaphylaxis, and rarely pneu- monly manifest as mild, self-limited cutaneous eruptions and monitis and meningitis. AERD is a clinical entity character- do not require any treatment.131 The mechanism of delayed ized by aspirin- and NSAID-induced respiratory reactions in skin reactions to RCM appears to be T-cell mediated.132 patients with chronic rhinosinusitis and asthma. The nomen- Rarely, more serious and life-threatening delayed reactions to clature ascribed to this type of reaction has included terms RCM have been described, such as SJS, TEN, and DRESS.599 such as aspirin sensitivity, aspirin intolerance, aspirin idio- syncrasy, aspirin-induced asthma, and aspirin triad.600 R. Aspirin and Nonsteroidal Anti-inflammatory Agents AERD does not fit precisely into a specific category of (NSAIDs) adverse drug reactions. AERD typically follows an illness Summary Statement 151: One type of adverse reaction to and starts as severe perennial rhinitis followed by the devel- aspirin and NSAIDs is AERD, a clinical entity characterized opment of nasal and/or sinus polyps, which then progress to by aspirin- and NSAID-induced respiratory reactions in pa- include symptoms of asthma.140 Rhinitis is often complicated tients with underlying asthma and/or rhinitis or sinusitis. (B) by chronic sinusitis, , and nasal polyposis. Asthma Summary Statement 152: The mechanism of AERD ap- and sensitivity to aspirin usually develop several years after pears to be related to aberrant arachidonic acid metabolism. the onset of rhinitis. Upper and lower respiratory tract symp- (B) toms are frequently sudden and severe after administration of Summary Statement 153: Controlled oral provocation with aspirin or any NSAID that inhibits the COX-1 enzyme. aspirin is considered to be the most conclusive way to con- Despite avoidance of aspirin and cross-reacting drugs, these firm the diagnosis of AERD. (B) patients typically experience refractory rhinosinusitis and Summary Statement 154: Aspirin and NSAIDs that inhibit asthma—in some cases requiring repeated sinus surgery pro- cyclooxygenase 1 (COX-1) cross-react and cause respiratory cedures and regular administration of oral steroids. AERD is reactions in AERD, whereas selective COX-2 inhibitors al- rare in asthmatic children and becomes increasingly more most never cause reactions in patients with AERD and can common in adults with asthma. Approximately 10% of adults typically be taken safely. (B) with asthma and a third of patients with asthma with nasal Summary Statement 155: Aspirin desensitization followed polyposis have AERD.601 by daily aspirin therapy to perpetuate the aspirin tolerant state The mechanism of AERD is related to aberrant arachidonic in patients with AERD is indicated in patients with AERD if acid metabolism. Before administration of aspirin, compared aspirin or NSAIDs are therapeutically necessary for treatment with non–aspirin-sensitive asthmatic patients, patients with of some other condition, such as cardiac or rheumatologic AERD have higher levels of both COX and 5-lipoxygenase diseases. (D) products, such as increased urinary leukotriene E4 and throm- Summary Statement 156: Aspirin desensitization followed boxane B2, and increased leukotriene E4 and B2 by daily aspirin has been associated with improved outcomes in bronchoalveolar lavage fluid.602-604 Patients with AERD in patients with AERD who are poorly controlled with med- also have increased respiratory tract expression of the cystei- ical and/or surgical management. (D) nyl leukotriene 1 receptor and heightened responsiveness to Summary Statement 157: 133,134 A second reaction type to aspirin inhaled leukotriene E4. A number of genetic polymor- and NSAIDs is exacerbation of urticaria and angioedema in phisms involving the leukotriene pathway have been reported approximately 20% to 40% of patients with underlying to be associated with AERD, including the chronic idiopathic urticaria. (C) Drugs that inhibit COX-1 promotor,605 cysteinyl leukotriene receptor 1 promotor,606 607 cross-react to cause this reaction, whereas selective COX-2 receptor related , and inhibitors typically are better tolerated by these patients. (C) receptor genes.608 However, not all of these findings have Summary Statement 158: A third reaction type to aspirin been replicated, and there is significant heterogeneity in study and NSAIDs is suggestive of an IgE-mediated mechanism populations (ie, Polish vs Korean populations).609 and manifests as urticaria or angioedema or anaphylaxis, and Administration of aspirin leads to inhibition of COX-1 it occurs in patients with no underlying respiratory or cuta- with resultant decrease in prostaglandin E2. Prostaglandin E2 neous disease. (C) These reactions appear to be drug specific normally inhibits 5-lipoxygenase, but with a loss of this and there is no cross-reactivity with other NSAIDs. (D) modifying effect, arachidonic acid molecules are preferen- Summary Statement 159: A fourth reaction type to aspirin tially metabolized in the 5-lipoxygenase pathway, resulting in and NSAIDs is urticaria or angioedema caused by all drugs increased production of cysteinyl leukotrienes. After aspirin that inhibit COX-1, and it occurs in patients without a prior challenge, patients with AERD have elevated levels of uri- history of chronic urticaria. (C) nary leukotriene E4, increased levels of histamine and leuko- Summary Statement 160: Rarely, patients exhibit com- triene C4 in nasal and bronchial secretions, and greatly up- bined (“blended”) respiratory and cutaneous reaction to as- regulated cysteinyl leukotriene receptors.602-604,610 Tryptase pirin or NSAIDs and hence cannot be classified into 1 the 4 and histamine are released into peripheral blood after aspirin reaction types described above. (C) administration, suggesting mast cell involvement.

273.e59 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY Aspirin and NSAIDs that inhibit COX-1 all cross-react and described herein is thought to play a pathogenic role. Selec- cause reactions in AERD. that are poor inhibitors tive COX-2 inhibitors are generally well tolerated in patients of COX-1 (eg, nonacetylated salicylates and acetaminophen) with chronic idiopathic urticaria, although there may be rare may cause reactions only if administered at high doses.611 exceptions.142-144 NSAIDs that preferentially inhibit COX-2 but also inhibit A third type of drug allergic reaction is aspirin or single COX-1 at higher doses may result in reactions, depending on NSAID-induced urticaria or angioedema or anaphylactic re- the dose given. Selective COX-2 inhibitors almost never action, in which case other NSAIDs are tolerated.145-147 The cause reactions in patients with AERD and can typically be underlying cause of these reactions is not fully understood. taken safely.135-139 The clinical pattern of a preceding period of sensitization There is no diagnostic in vitro or skin test for AERD. The during which the drug is tolerated suggests an IgE-mediated diagnosis is usually established by history, but if the history mechanism, but attempts to detect drug specific IgE have is unclear or when definite diagnosis is required, a controlled been unsuccessful in most cases. However, a recent investi- oral provocation challenge with aspirin may be performed. gation of 53 patients experiencing systemic symptoms 30 When patients with a history suggestive of AERD (ie, minutes after ingestion of a pyrazolone () asthma, rhinosinusitis, and history of respiratory reaction to revealed positive skin and enzyme-linked immunosorbent aspirin or aspirin-like drug) are challenged with aspirin, ap- assay in vitro test results in 51 of the 53 patients.616 These proximately 85% will have a respiratory reaction confirming specific IgE tests were specific in that other pyrazolone the diagnosis.140 A recent study showed that 100% of patients derivatives (antipyrine, , or metamizol) were with a history of aspirin causing a severe reaction (poor unable to inhibit IgE binding in the in vitro system. The response to albuterol with need for medical intervention) had reaction is not due to arachidonic acid dysfunction, and any positive oral aspirin challenges.141 NSAID, including selective COX-2 inhibitors, may be re- Management of patients with AERD involves avoidance of 617,618 aspirin and NSAIDs and aggressive medical and/or surgical sponsible. Patients with a history of acute urticaria to aspirin are at increased risk for the subsequent development treatment of underlying asthma and rhinitis or sinusitis. A 619 pharmacologic induction of drug tolerance procedure (also of chronic urticaria. known as aspirin desensitization), during which tolerance to A fourth type of drug allergic reaction of aspirin or NSAID aspirin can be induced and maintained, is an important ther- allergy is urticaria or angioedema due to aspirin and any apeutic option for patients with AERD. This procedure en- NSAID that inhibits COX-1 and thus differs from the afore- tails administration of incremental oral doses of aspirin mentioned type of reaction in that it is nonselective. This type throughout several days, until a dosage of 650 mg (2 tablets) of reactions also occurs in individuals without a prior history of aspirin can be taken without adverse reaction. Induction of of chronic urticaria.364,620 These patients are usually able to drug tolerance of patients with AERD may be appropriate if tolerate COX-2 inhibitors, and their reactions are purely cuta- aspirin or NSAIDs is therapeutically necessary or if their neous without accompanying anaphylactic symptoms.142-144 respiratory disease is poorly controlled with medical and/or Patients with a history of acute urticaria to multiple NSAIDs surgical management. Aspirin desensitization treatment im- are also at increased risk for the development of chronic proves clinical outcomes for both upper and lower respiratory urticaria.619 tract disease.247,360,361 During long-term aspirin desensitiza- Rarely, patients exhibit combined (“blended”) respiratory tion, urinary leukotriene E4 decreases to baseline levels, bron- and cutaneous reaction to aspirin or NSAIDs and hence chial responsiveness to leukotriene E4 is greatly reduced, cannot be classified into 1 of the 4 reaction types described serum histamine and tryptase levels decrease, leukotriene C4 herein. In addition, drug allergic reactions to aspirin or and histamine in nasal secretions disappears, and there is a NSAIDs can rarely manifest as pneumonitis or meningitis. decrease in the number of respiratory cells expressing the These reactions appear to be drug specific, and avoidance of cysteinyl leukotriene 1 receptor.133,134,610,612,613 all NSAIDs is not necessary.621 A second clinical presentation of aspirin and NSAID drug Allergic rashes are common adverse effects of clopidogrel, a allergic reactions is an exacerbation of urticaria or angio- thiopyridine inhibitor of platelet activation that is often recom- edema in patients with chronic idiopathic urticaria. Approx- mended in aspirin-intolerant patients.622-624 Although the mech- imately 20% to 40% of patients with chronic idiopathic anisms of such reactions are unknown, successful oral induction urticaria develop a worsening of their condition after expo- of drug tolerance protocols have been reported.622,624 614,615 sure to aspirin or NSAIDs. The rate appears to be more Quinine-induced angioedema may occur in aspirin-intoler- frequent in patients in an active phase of their urticaria or ant patients.625 angioedema syndrome. Most patients with a history of exac- erbations induced by aspirin or NSAIDs demonstrated the S. Angiotensin-Converting Enzyme (ACE) Inhibitors presence of histamine-releasing factors assessed by autolo- Summary Statement 161: ACE inhibitors are associated gous serum skin tests and basophil histamine release as- with 2 major adverse effects—cough and angioedema. (C) says.309 All drugs that inhibit COX-1 cross-react to cause this Summary Statement 162: ACE inhibitor–related cough of- reaction, and the arachidonic acid metabolism dysfunction ten begins within the first few weeks of treatment and occurs

VOLUME 105, OCTOBER, 2010 273.e60 in up to 20% of patients, particularly women, blacks, and istration of ACE inhibitors and they should not receive these Asians. (C) drugs. The temporal relationship between initiation of ther- Summary Statement 163: The mechanism of ACE inhibi- apy with ACE inhibitors and occurrence of angioedema is tor–related cough is unclear. The cough resolves with discon- unpredictable and differs from the temporal pattern of other tinuation of the drug therapy in days to weeks. (D) adverse drug reactions. Patients typically take ACE inhibitors Summary Statement 164: Patients with ACE inhibitor– for months or even years before angioedema occurs.156 It is related cough are able to tolerate angiotensin II receptor also puzzling that recurrent episodes of angioedema occur blockers (ARBs). (A) sporadically despite continued daily use of ACE inhibitors. Summary Statement 165: ACE inhibitor–induced angio- ACE inhibitor–associated angioedema is often difficult to edema occurs in approximately 0.1% to 0.7% of patients and manage. Treatment includes discontinuing use of the medi- is most common in blacks. (C) cation and supportive care with careful management of the Summary Statement 166: ACE inhibitor–induced angio- airway. Selected cases of refractory ACE inhibitor–induced edema frequently involves the face and oropharynx and can angioedema have been successfully treated with infusion of be life-threatening or fatal. (C) .629 Most patients with angioedema related Summary Statement 167: The mechanism of ACE inhibi- to ACE inhibitor usually tolerate ARBs. There are, however, tor–induced angioedema may be related to interference with bradykinin degradation. It may take months or years after case reports of occasional patients who continue to experi- ence angioedema after being switched from ACE inhibitors to initiation of therapy for a reaction to appear and often occurs 630,631 sporadically despite persistent treatment. (C) ARBs. Because there is no diagnostic test to prove Summary Statement 168: ACE inhibitor–induced angio- whether angioedema in a given patient is truly due to use of edema is treated with discontinuation of the drug therapy and an ACE inhibitor (rather than idiopathic), these cases may not subsequent avoidance of all ACE inhibitors. (D) represent true cross-reactivity between these agents. Summary Statement 169: Most patients who experience T. Biologic Modifiers angioedema during ACE inhibitor treatment are able to tol- In the past decade, a number of biologic agents have been erate ARBs. (C) developed to neutralize proinflammatory cytokines, their cel- Summary Statement 170: Patients with a history of angio- lular receptors, and IgE antibody.157,158 Because the clinical edema or C1 esterase inhibitor deficiency are at increased risk experience with these drugs varies (ie, phase IV experiences), of more frequent and severe episodes of angioedema with the the spectrum of reported allergic reactions may not yet be administration of ACE inhibitors, so they should not receive these drugs. (C) fully known for all of them. A separate type of classification for adverse reactions to biological agents has been proposed ACE inhibitors have 2 major adverse effects—cough and 159 angioedema. Cough occurs in up to 20% of patients, is based on the mechanism of reactions (Table 3). High-dose typically dry and nonproductive, and occurs more commonly reactions are related to high cytokine levels administered in women, blacks, and Asians.149 The cough generally begins directly or from cytokines released (cytokine release syn- within the first few weeks of treatment, but occasionally the drome). Hypersensitivity reactions may be either antibody or onset may occur much later. Aside from enzymatically con- cell mediated. Immune or cytokine dysregulation may result verting angiotensin 1 to angiotensin 2, ACE inhibitors also in secondary immunodeficiency, autoimmunity, or allergic or normally metabolize bradykinin. ACE inhibitors allow the atopic disorders. Cross-reactive reactions may occur when accumulation of bradykinin, which may cause stimulation of the biologic agent is intended for a pathologic cell type but vagal afferent fibers to produce cough. Bradykinin has cross-reacts with normal cells. Finally, biologics may also also been shown to induce the production of arachidonic acid result in nonimmunologic adverse effects. metabolites and , and these products may contrib- 1. Cytokines ute to cough production through proinflammatory mecha- nisms.149 ARBs are not associated with development of Summary Statement 171: Allergic drug reactions ranging cough, the incidence of which is comparable to treatment from cutaneous lesions to severe anaphylaxis may occur with either placebo or diuretics.626-628 There are no controlled during treatment with recombinant interferons. (C) ␣ ␤ studies on potential medical treatment of ACE inhibitor– Both - and -interferons have been associated with a induced cough in patients who require continued treatment. variety of allergic drug events. Cutaneous lesions include The incidence of angioedema with ACE inhibitors is ap- urticaria, atopic dermatitis, eczematous reactions at injection proximately 0.1% to 0.7%149,150 and appears to be more com- sites, leukocytoclastic vasculitis, and fixed drug eruption.632-637 mon in blacks.151,152 The angioedema frequently involves the Visceral adverse events include pulmonary vasculitis and face or upper airway and can be life-threatening or fatal.153,154 autoimmune hepatitis.638,639 Life-threatening events, such as Reports of angioedema of the intestinal tract secondary to angioedema and anaphylaxis, have been reported.640,641 ACE inhibitors have also been described.155 Patients with C1 Allergic mechanisms may or may not play a role in throm- esterase inhibitor deficiency are at increased risk of more botic or hemolytic uremic syn- frequent and severe episodes of angioedema with the admin- drome and systemic capillary permeability syndrome associ-

273.e61 ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY ated with the use of and colony- imab heavy chain. In most of these patients, specific IgE cetux- stimulating factor, respectively.642,643 imab antibodies were present in patients’ sera before therapy.184 A fatal hypersensitivity reaction after infusion of gemtuzumab 2. Anti–TNF-␣ Drugs oxogamicin followed by irradiated was recently re- Summary Statement 172: Both cutaneous and systemic ported.651 There have been several recent reports of immune- allergic reactions have been reported after treatment with mediated hemolytic anemia after injections of anti-CD11a (the ␣ infliximab, a human monoclonal antibody against tumor ne- subunit of leukocyte function–associated antigen 1) monoclonal crosis factor ␣ (TNF-␣). (C) antibody ().652 Such reactions should be clearly dis- A variety of immune-mediated reactions have occurred tinguished from cytokine release or acute respiratory distress during infliximab (Remicade) treatment for adult and juvenile syndromes caused by other monoclonal antibodies (eg, ritux- , Crohn’s disease, and psoriasis. These imab).186 However, severe serum sickness–like reactions have include urticaria, flare-up of atopic dermatitis, maculopapular been reported after infusions of rituximab and natalizumab.653,654 rashes, leukocytoclastic vasculitis, serum sickness, and at least 7 In 2006, 3 patients treated with natalizumab developed progres- instances of life-threatening anaphylactic reactions.160-173 Se- sive multifocal leukoencephalopathy, resulting in 2 deaths.655 vere adverse reactions, including anaphylaxis and progressive Depending on the monoclonal antibody and type of reac- multifocal leukoencephalopathy, appear to be common in tion, readministration strategies may include medication pre- young (Ͻ10 years of age) children.644 A recent retrospective treatment, slowing infusion rates, or induction of drug toler- evaluation of safety with this agent revealed that immediate ance.184 In patients with immediate-type reactions, successful hypersensitivity reactions (9/84 or 11%) were a major reason induction of tolerance to rituximab, infliximab, and trastu- for discontinuation of the drug therapy.645 A subset of patients zumab has been reported using a 6-hour protocol in combi- experienced allergic reactions as a result of antibodies to nation with corticosteroid and antihistamine premedication. infliximab.175 Other possible immunologically related reac- tions include the Guillain-Barré syndrome, peripheral neu- 4. Omalizumab ropathy, and demyelinating syndromes.646,647 Fewer adverse Summary Statement 174: Rare anaphylactic reactions to effects have been associated with adalimumab (Humira), anti-IgE humanized monoclonal antibody (omalizumab) were another recently available fully humanized TNF-␣ monoclo- described during phase 3 clinical trials and during the post- nal antibody. These include injection site pruritic rashes and marketing surveillance period. (C) new-onset asthma.174,175 New-onset asthma may also appear A combined review of spontaneous postmarketing adverse during treatment with both infliximab and etanercept (En- events from the US Food and Drug Administration Adverse brel). Immune-mediated reactions have also been rarely as- Event Reporting System, records of the manufacturers of sociated with the latter agent, a recombinant TNF-␣ extra- omalizumab, and published cases through December 2006 cellular protein domain fused to human IgG1 Fc, which revealed 124 cases of anaphylaxis associated with this neutralizes soluble TNF-␣. These include urticaria, rashes, drug.656 Many cases experienced either delayed onset (Ͼ2 injection site reactions, leukocytoclastic vasculitis, lupus ery- hours) or protracted progression of signs and symptoms after thematosus, and 1 instance of lung granulomatosis injury.176-182 dose administration. A contemporaneous review of omali- zumab (Xolair; Genentech) clinical trials and postmarketing 3. Monoclonal Antibodies surveillance data by a joint task force of the major US allergy Summary Statement 173: Both cutaneous and systemic societies between June 1, 2003, and December 31, 2005, allergic reactions have been reported after treatment with revealed 41 episodes of anaphylaxis in 35 patients. Because both murine and humanized monoclonal antibodies. (C) 39,510 patients in this database received omalizumab during Documented episodes of anaphylaxis after administration of a the same period, this corresponded to a reporting rate of chimeric anti–interleukin 2 receptor antagonist monoclonal an- 0.103% of anaphylactic episodes.187 It is noteworthy that 83 tibody () and muromonab (murine anti-CD3 mono- additional anaphylactic instances were reported in the 1-year clonal antibody of the IgG2a class [OKT3]) have occurred.545,648 interval between these 2 surveys. The Omalizumab Joint A patient who had experienced anaphylaxis to basiliximab sub- Task Force report recommended that patients receiving oma- sequently tolerated a humanized version () with im- lizumab should be directly observed, in a physician’s office, punity.649 It is not yet evident whether severe allergic reactions after receiving omalizumab for 2 hours following the first 3 will occur after use of , a fully humanized anti-CD3 doses and 30 minutes after subsequent doses.187 monoclonal antibody now in phase 1 studies.650 Hypersensitivity reactions to cetuximab (chimeric mouse-human IgG1 monoclo- 5. Anticancer Monoclonal Antibodies nal antibody against the epidermal growth factor receptor), in- Summary Statement 175: The cytokine release syndrome cluding IgE-mediated anaphylaxis, has been reported to occur at must be distinguished between anaphylactoid and anaphylac- a national rate of 3% or less but much higher (22%) in the Mid tic reactions due to anticancer monoclonal antibodies. (C) South region of the United States.183 IgE antibodies in this The development of monoclonal antibodies for the treat- condition are specific for an oligosaccharide galactose-␣-1, ment of malignant has increased rapidly in the past 3-galactose, which is present on the Fab portion of the cetux- decade.657,658 These include rituximab (anti-CD20), trastu-

VOLUME 105, OCTOBER, 2010 273.e62 zumab (anti–HER-2), and (anti-CLL) among patients (48%) who received this treatment experienced ana- others. Severe symptoms, such as fever, rigors, chills, and the phylactoid reactions.669 Most of these reactions occurred acute respiratory distress syndrome, may occur during admin- within the first 15 minutes. Anaphylactoid reactions and istration of the first dose of the drug due to a cytokine release deaths have been associated with intravenous iron prepara- syndrome.185,186 An extreme example of a life-threatening tions.670 According to a US Food and Drug Administration cytokine storm occurred in 6 healthy volunteers after receiv- surveillance database, all-event and all-fatal reporting events ing a superagonistic anti-CD28 monoclonal antibody.659 Im- were highest, intermediate, and very low after administration mune-mediated reactions, including anaphylaxis and throm- of iron-dextran, sodium ferric gluconate, and iron sucrose bocytopenia, have also been reported.660-662 Successful preparations, respectively.670 induction of drug tolerance to HER-2 monoclonal antibody In recent years, life-threatening anaphylactic reactions has been documented.663 The cytokine release syndrome also have occurred after intravenous use of isosulfan blue and occurred after dosing with antisense oligonucleotides in pa- Patent Blue V dyes, an adjunctive diagnostic lymphangio- tients with advanced leukemia.664 graphic agent.671-673 The results of epicutaneous skin testing and, if required, intradermal skin testing are positive in most U. Complementary Medicines patients.673 differs structurally from both Summary Statement 176: Allergic reactions may occur isosulfan blue and Patent Blue V, and anaphylactic reactions after use of complementary medicines such as bee pollen, are rare. A recent of 3 patients with echinacea, and vitamins. (C) systemic reactions to Patent Blue V dye demonstrated epicu- The term complementary medicine includes herbal prod- taneous skin test cross-reactivity to methylene blue dye.671 ucts, vitamins, minerals, amino acids, and essential oils.188 However, confirmatory challenges were never performed, There is widespread belief that these products are safe be- and therefore a determination of the positive and negative cause they are “natural.”189 However, well-recognized ad- predictive values of such testing requires further evaluation. verse effects, including anaphylaxis, have been reported in Anaphylactoid reactions have been described after admin- patients using bee pollen products.190 Allergic reactions, in- istration of colloid volume expanders (dextran, gelatin, hy- cluding asthma and anaphylaxis, have been reported after droxyethyl starch, and human serum albumin).578 An effec- ingestion of echinacea, an herb that is derived from several tive graded challenge protocol may be used to prevent severe species of a .191 A variety of cutaneous reac- anaphylactoid reactions to dextran contained in iron-dextran tions and 1 instance of TEN have been reported after use of complexes.674 This may be life saving in patients who require Chinese herbal medications, which sometimes have been parenteral iron. Life-threatening reactions to the osmotic di- adulterated with synthetic medications.192,193 Herbal products, uretic mannitol is most likely due to hyperosmolar-dependent homeopathic remedies. and multivitamin-mineral complexes histamine release. Systemic anaphylactoid reactions may oc- may be a potential risk for systemic contact dermatitis in cur after parenteral administration of Cremophor-EL, a sol- nickel and allergic patients.665,666 Because the extent vent for paclitaxel, cyclosporine, and some anes- of this problem is unknown, patients should be questioned thetics. There are also anecdotal reports of reactions to about the use of herbs and health supplements. Anaphylactic sodium benzoate and chlorobutanol, which are used as pre- reactions to vitamins (particularly B1 and B2) are extremely servatives in various biologicals. rare.667 The incidence of anaphylaxis to intravenous phyton- Some preservatives may evoke cough and bronchocon- striction in susceptible asthmatic patients after exposure to adione ( K1) solubilized in Cremophor-EL was 3 per 10,000 doses.668 nebulizer solutions or formulations containing benzalkonium chloride or sulfites.206 It has been suggested that susceptibility V. Other Agents to sulfites in some asthmatic patients may be due to a defi- Summary Statement 177: N-acetylcysteine may cause ana- ciency of sulfite oxidase; however, most cases are due to phylactoid reactions. (C) generation of dioxide in the oropharynx.675 Anecdotal Summary Statement 178: Anaphylactoid reactions and instances of anaphylaxis or severe asthma have been reported deaths have been associated with intravenous iron prepara- in milk or soy allergic patients after of specific dry tions, particularly iron-dextran. (C) powder formulated metered dose .676,677 A large ran- Summary Statement 179: Life-threatening anaphylactic re- domized controlled study revealed that paradoxical broncho- actions have occurred after intravenous use of isosulfan blue constriction occurred more often after inhalation of metered and Patent Blue V dyes. (C) dose inhalers containing soy-derived lecithin and oleic acid Summary Statement 180: Anaphylactoid reactions may than one with alone.677 In a case report, it was occur after treatment with colloid volume expanders, manni- demonstrated that anaphylactic reactions may occur due to tol, Cremophor-EL, and preservatives. (C) use of a -containing dry powder in a milk Summary Statement 181: Preservatives and additives in allergic patient.676 In vitro and in vivo testing demonstrated medications rarely cause immunologic drug reactions. (C) presence of milk protein in the dry powder device used by the N-acetylcysteine is the treatment of choice for patient.676 This illustrates that food allergens may be hidden overdosage. In a prospective case controlled study, 31/64 excipients in commonly used drug formulations.

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